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![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Papillary Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
PAP‑8
• Rising or newly elevated Tg and
negative imaging
• Non‑resectable tumors
• Non‑radioiodine responsivez
Suppress TSH with levothyroxinej
Locoregional
recurrence
Surgery (preferred) if resectablebb
and
Consider Radioiodine treatment,aa if postoperative radioiodine imaging positive
or
Disease monitoring for non‑progressive disease that is stable and distant from
critical structures
or
For select patients with unresectable, non–radioiodine‑avid, and progressive disease,
consider:
EBRT (IMRT/stereotactic body radiation therapy [SBRT])n
and/or
Systemic therapies (Treatment of Metastatic Disease PAP‑9)
or
For select patients with limited burden nodal disease, consider local therapies when
available (ethanol ablation, radiofrequency ablation [RFA])
Metastatic disease
RAI therapy for iodine-avid diseasen
and/or
Local therapies when availablecc
and/or
If not amenable to RAI (Treatment of Metastatic Disease PAP‑9)
RECURRENT DISEASE
Continue surveillance with
unstimulated Tg,
ultrasound, and other imaging as
clinically indicated (PAP‑7)
• Progressively rising Tg (basal or stimulated)
• Scans (including PET) negative
Consider radioiodine therapy with ≥100 mCiaa
and
Post‑treatment iodine-131 imaging (category 3); additional RAI treatments should be
limited to patients who responded to previous RAI therapy (minimum of 6–12 months
between RAI treatments)
Consider preoperative
iodine total body scan
aa
The administered activity of RAI therapy should be adjusted
for pediatric patients. Principles of Radiation and RAI
Therapy (THYR-C).
bb Preoperative vocal cord assessment, if central neck
recurrence.
cc Ethanol ablation, cryoablation, RFA, etc.
j Principles of TSH Suppression (THYR‑A).
n Principles of Radiation and RAI Therapy (THYR-C).
z
Generally, a tumor is considered iodine‑responsive if follow‑up iodine-123 or low‑dose iodine-131 (1–3
mCi) whole body diagnostic imaging done 6–12 mo after iodine-131 treatment is negative or shows
decreasing uptake compared to pre‑treatment scans. It is recommended to use the same preparation
and imaging method used for the pre‑treatment scan and therapy. Favorable response to iodine-131
treatment is additionally assessed through change in volume of known iodine‑concentrated lesions by
CT/MRI, and by decreasing unstimulated or stimulated Tg levels.
Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.](https://image.slidesharecdn.com/thyroid-221220101008-dd5cd148/85/thyroid-pdf-17-320.jpg)
![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Papillary Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
PAP‑9
CNS metastases
(PAP‑11)
TREATMENT OF LOCALLY RECURRENT, ADVANCED, AND/OR METASTATIC DISEASE NOT AMENABLE TO RAI THERAPY
j Principles of TSH Suppression (THYR‑A).
n Principles of Radiation and RAI Therapy (THYR-C).
cc Ethanol ablation, cryoablation, RFA, etc.
dd
Kinase inhibitor therapy may not be appropriate for patients with stable or slowly
progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B).
ee
Commercially available small‑molecule kinase inhibitors (such as axitinib,
everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or
dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical
trials are not available or appropriate.
ff
Cytotoxic chemotherapy has been shown to have minimal efficacy, although most
studies were small and underpowered.
Structurally
persistent/recurrent
locoregional or
distant metastatic
disease not
amenable to RAI
therapy
Bone
metastases
(PAP‑10)
Soft tissue
metastases
(eg, lung, liver,
muscle) excluding
central nervous
system (CNS)
metastases (see
below)
• Continue to
suppress TSH with
levothyroxinej
• For advanced,
progressive, or
threatening disease,
genomic testing to
identify actionable
mutations (including
ALK, NTRK, and
RET gene fusions),
DNA mismatch
repair (dMMR),
microsatellite
instability (MSI), and
tumor mutational
burden (TMB)
• Consider clinical trial
• Consider systemic therapy for progressive and/or symptomatic
disease
Preferred Regimens
◊ Lenvatinib (category 1)dd
Other Recommended Regimens
◊ Sorafenib (category 1)dd
Useful in Certain Circumstances
◊ Cabozantinib (category 1) if progression after lenvatinib and/
or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene
fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion
positive tumors
◊ Pembrolizumab for patients with tumor mutational burden-
high (TMB-H) (≥10 mutations/megabase [mut/Mb]) tumors
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation
that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for
progressive and/or symptomatic disease if clinical trials or
other systemic therapies are not available or appropriateee,ff
• Consider resection of distant metastases and/or EBRT (SBRT/
IMRTn/other local therapiescc when available to metastatic
lesions if progressive and/or symptomatic (Locoregional disease
PAP‑8)
• Disease monitoring is often appropriate in asymptomatic patients
with indolent disease assuming no brain metastasisdd (PAP‑7)
• Best supportive care, see the NCCN Guidelines for Palliative Care
Unresectable
locoregional
recurrent/
persistent disease
Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.](https://image.slidesharecdn.com/thyroid-221220101008-dd5cd148/85/thyroid-pdf-18-320.jpg)
![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Papillary Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
PAP‑10
• Consider surgical palliation and/or EBRT/SBRT/other local therapiescc when available if symptomatic, or asymptomatic in
weight‑bearing sites. Embolization prior to surgical resection of bone metastases should be considered to reduce the risk of
hemorrhage
• Consider embolization or other interventional procedures as alternatives to surgical resection/EBRT/IMRT in select cases
• Consider intravenous bisphosphonate or denosumabhh
• Disease monitoring may be appropriate in asymptomatic patients with indolent diseasedd (PAP‑7)
• Consider systemic therapy for progressive and/or symptomatic disease
Preferred Regimens
◊ Lenvatinib (category 1)dd
Other Recommended Regimens
◊ Sorafenib (category 1)dd
Useful in Certain Circumstances
◊ Cabozantinib (category 1) if progression after lenvatinib and/or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors
◊ Pembrolizumab or patients with TMB-H (≥10 mut/Mb) tumors
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other
systemic therapies are not available or appropriatedd,ee,ff
• Best supportive care, see the NCCN Guidelines for Palliative Care
Bone
metastases
TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYgg
ccEthanol ablation, cryoablation, RFA, etc.
dd Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive
indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B).
ee
Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus,
pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive]
[all are category 2A]) can be considered if clinical trials are not available or appropriate.
ff Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were
small and underpowered.
gg
RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease.
hh
Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia;
patients with hypoparathyroidism and vitamin D deficiency are at increased risk of
hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures.
Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.](https://image.slidesharecdn.com/thyroid-221220101008-dd5cd148/85/thyroid-pdf-19-320.jpg)
![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Papillary Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
PAP‑11
TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYgg
• For solitary CNS lesions, either neurosurgical resection or stereotactic radiosurgeryn is preferred or
• For multiple CNS lesions, consider radiotherapy, including whole brain radiotherapy or stereotactic radiosurgery,n and/or
resection in select cases
and/or
• Consider systemic therapy for progressive and/or symptomatic disease
Preferred Regimens
◊ Lenvatinib (category 1) dd,ii,jj
Other Recommended Regimens
◊ Sorafenib (category 1) dd,ii,jj
Useful in Certain Circumstances
◊ Cabozantinib (category 1) if progression after lenvatinib and/or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors
◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors
and/or
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other
systemic therapies are not available or appropriatedd,ee,ff,hh
• Best supportive care, see the NCCN Guidelines for Palliative Care
CNS
metastases
n Principles of Radiation and RAI Therapy (THYR-C).
dd Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive
indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B).
ee
Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus,
pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive]
[all are category 2A]) can be considered if clinical trials are not available or appropriate.
ff Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were
small and underpowered.
gg
RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease.
hh
Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia;
patients with hypoparathyroidism and vitamin D deficiency are at increased risk of
hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures.
ii
After consultation with neurosurgery and radiation oncology, data on the efficacy of lenvatinib or
sorafenib for patients with brain metastases have not been established.
jj
Tyrosine kinase inhibitor (TKI) therapy should be used with caution in otherwise untreated CNS
metastases due to bleeding risk.
Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.](https://image.slidesharecdn.com/thyroid-221220101008-dd5cd148/85/thyroid-pdf-20-320.jpg)
![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Follicular Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
Unresectable
locoregional
recurrent/
persistent disease
CNS metastases
(FOLL‑10)
TREATMENT OF LOCALLY RECURRENT, ADVANCED, AND/OR METASTATIC DISEASE NOT AMENABLE TO RAI THERAPY
• Consider systemic therapy for progressive and/or symptomatic
disease
Preferred Regimens
◊ Lenvatinib (category 1)bb
Other Recommended Regimens
◊ Sorafenib (category 1)bb
Useful in Certain Circumstances
◊ Cabozantinib if progression after lenvatinib and/or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene
fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion
positive tumors
◊ Pembrolizumab for patients with tumor mutational burden-
high (TMB-H) (≥10 mutations/megabase [mut/Mb]) tumors
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation
that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for
progressive and/or symptomatic disease if clinical trials or
other systemic therapies are not available or appropriatecc,dd
• Consider resection of distant metastases and/or EBRT (SBRT/
IMRT)i/other local therapiesaa when available to metastatic
lesions if progressive and/or symptomatic. (Locoregional disease
FOLL‑7)
• Disease monitoring is often appropriate in asymptomatic patients
with indolent disease assuming no brain metastasis.dd (FOLL‑6)
• Best supportive care, see the See NCCN Guidelines for Palliative
Care
f See Principles of TSH Suppression (THYR‑A).
i See Principles of Radiation and RAI Therapy (THYR-C).
aa Ethanol ablation, cryoablation, RFA, etc.
bb
Kinase inhibitor therapy may not be appropriate for patients with stable or
slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy
(THYR‑B).
cc Commercially available small‑molecule kinase inhibitors (such as axitinib,
everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or
dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical
trials are not available or appropriate.
dd Cytotoxic chemotherapy has been shown to have minimal efficacy, although
most studies were small and underpowered.
FOLL‑8
Structurally
persistent/recurrent
locoregional or
distant metastatic
disease not
amenable to RAI
therapy
Bone metastases
(FOLL‑9)
• Continue to
suppress TSH with
levothyroxinef
• For advanced,
progressive, or
threatening disease,
genomic testing to
identify actionable
mutations
(including ALK,
NTRK, and RET
gene fusions),
dMMR, MSI, and
TMB
• Consider clinical
trial
Soft tissue
metastases (eg,
lung, liver, muscle)
excluding CNS
metastases (see
below)
Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.](https://image.slidesharecdn.com/thyroid-221220101008-dd5cd148/85/thyroid-pdf-28-320.jpg)
![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Follicular Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
FOLL‑9
TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYee
• Consider surgical palliation and/or EBRT/SBRT/other local therapiesaa when available if symptomatic, or asymptomatic in
weight‑bearing sites. Embolization prior to surgical resection of bone metastases should be considered to reduce the risk of
hemorrhage
• Consider embolization or other interventional procedures as alternatives to surgical resection/EBRT/IMRT in select casesi
• Consider intravenous bisphosphonate or denosumabff
• Disease monitoring may be appropriate in asymptomatic patients with indolent diseasebb (FOLL‑6)
• Consider systemic therapy for progressive and/or symptomatic disease
Preferred Regimens
◊ Lenvatinib (category 1)bb
Other Recommended Regimens
◊ Sorafenib (category 1)bb
Useful in Certain Circumstances
◊ Cabozantinib if progression after lenvatinib and/or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors
◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other
systemic therapies are not available or appropriatebb,cc,dd
• Best supportive care, see the NCCN Guidelines for Palliative Care
Bone
metastases
i See Principles of Radiation and RAI Therapy (THYR-C).
aa Ethanol ablation, cryoablation, RFA, etc.
bb
Kinase inhibitor therapy may not be appropriate for patients with stable or
slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy
(THYR‑B).
cc
Commercially available small‑molecule kinase inhibitors (such as axitinib,
everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or
dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical
trials are not available or appropriate.
dd
Cytotoxic chemotherapy has been shown to have minimal efficacy, although
most studies were small and underpowered.
ee
RAI therapy is an option in some patients with bone metastases and RAI-
sensitive disease.
ff
Denosumab and intravenous bisphosphonates can be associated with severe
hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at
increased risk of hypocalcemia. Discontinuing denosumab can cause rebound
atypical vertebral fractures.
TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYee
Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.](https://image.slidesharecdn.com/thyroid-221220101008-dd5cd148/85/thyroid-pdf-29-320.jpg)
![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Follicular Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
i Principles of Radiation and RAI Therapy (THYR-C).
aa Ethanol ablation, cryoablation, RFA, etc.
bb
Kinase inhibitor therapy may not be appropriate for patients with stable or slowly
progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B).
cc
Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus,
pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF
positive] [all are category 2A]) can be considered if clinical trials are not available or
appropriate.
dd
Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies
were small and underpowered.
ee
RAI therapy is an option in some patients with bone metastases and RAI-sensitive
disease.
ff
Denosumab and intravenous bisphosphonates can be associated with severe
hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased
risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral
fractures.
gg
After consultation with neurosurgery and radiation oncology; data on the efficacy of
lenvatinib or sorafenib for patients with brain metastases have not been established.
hh TKI therapy should be used with caution in otherwise untreated CNS metastases due to
bleeding risk.
FOLL‑10
CNS
metastases
• For solitary CNS lesions, either neurosurgical resection or stereotactic radiosurgery is preferred
or
• For multiple CNS lesions, consider radiotherapy,i including whole brain radiotherapy or stereotactic radiosurgery,i and/or
resection in select cases
and/or
• Consider systemic therapy for progressive and/or symptomatic disease
Preferred Regimens
◊ Lenvatinib (category 1)bb,gg,hh
Other Recommended Regimens
◊ Sorafenib (category 1) bb,gg,hh
Useful in Certain Circumstances
◊ Cabozantinib if progression after lenvatinib and/or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors
◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors
and/or
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or
other systemic therapies are not available or appropriatebb,cc,dd,ff
• Best supportive care, see the NCCN Guidelines for Palliative Care
TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYee
Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.](https://image.slidesharecdn.com/thyroid-221220101008-dd5cd148/85/thyroid-pdf-30-320.jpg)
![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Hürthle Cell Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
HÜRT‑8
Unresectable
locoregional
recurrent/
persistent disease
Soft tissue
metastases
(eg, lung, liver,
muscle) excluding
CNS metastases
(see below)
CNS
metastases
(HÜRT‑10)
TREATMENT OF LOCALLY RECURRENT, ADVANCED, AND/OR METASTATIC DISEASE NOT AMENABLE TO RAI THERAPY
• Consider systemic therapy for progressive and/or symptomatic
disease
Preferred Regimens
◊ Lenvatinib (category 1)cc
Other Recommended Regimens
◊ Sorafenib (category 1)cc
Useful in Certain Circumstances
◊ Cabozantinib if progression after lenvatinib and/or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene
fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion
positive tumors
◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation
that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for
progressive and/or symptomatic disease if clinical trials or
other systemic therapies are not available or appropriatedd,ee
• Consider resection of distant metastases and/or EBRT (SBRT/
IMRT)j/other local therapiesbb when available to metastatic
lesions if progressive and/or symptomatic (Locoregional disease,
HÜRT‑7)
• Disease monitoring is often appropriate in asymptomatic patients
with indolent disease assuming no brain metastasiscc (HÜRT‑6)
• Best supportive care, see the NCCN Guidelines for Palliative Care
f Principles of TSH Suppression (THYR‑A).
j Principles of Radiation and RAI Therapy (THYR-C).
bb Ethanol ablation, cryoablation, RFA, etc.
cc
Kinase inhibitor therapy may not be approriate for patients with stable or slowly
progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B).
dd
Commercially available small‑molecule kinase inhibitors (such as axitinib,
everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or
dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical
trials are not available or appropriate.
ee
Cytotoxic chemotherapy has been shown to have minimal efficacy, although
most studies were small and underpowered.
Structurally
persistent/
recurrent
locoregional
or distant
metastatic
disease not
amenable to
RAI therapy
Bone metastases
(HÜRT‑9)
• Continue to
suppress
TSH with
levothyroxinef
• For advanced,
progressive,
or threatening
disease, genomic
testing to identify
actionable
mutations
(including ALK,
NTRK, and RET
gene fusions),
dMMR, MSI, and
TMB
• Consider clinical
trial
Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.](https://image.slidesharecdn.com/thyroid-221220101008-dd5cd148/85/thyroid-pdf-38-320.jpg)
![Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network®
(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Hürthle Cell Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
• Consider surgical palliation and/or EBRT/SBRT/other local therapiesbb when available if symptomatic, or asymptomatic in
weight‑bearing sites. Embolization prior to surgical resection of bone metastases should be considered to reduce the risk of
hemorrhage
• Consider embolization or other interventional procedures as alternatives to surgical resection/EBRT/IMRT in select casesj
• Consider intravenous bisphosphonate or denosumabgg
• Disease monitoring may be appropriate in asymptomatic patients with indolent diseaseee (HÜRT‑6)
• Consider systemic therapy for progressive and/or symptomatic disease
Preferred Regimens
◊ Lenvatinib (category 1)cc
Other Recommended Regimens
◊ Sorafenib (category 1)cc
Useful in Certain Circumstances
◊ Cabozantinib if progression after lenvatinib and/or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors
◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other
systemic therapies are not available or appropriatecc,dd,ee
• Best supportive care, see the NCCN Guidelines for Palliative Care
Bone
metastases
TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYff
HÜRT‑9
j Principles of Radiation and RAI Therapy (THYR-C).
bb Ethanol ablation, cryoablation, RFA, etc.
cc
Kinase inhibitor therapy may not be appropriate for patients with stable or slowly
progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B).
dd Commercially available small‑molecule kinase inhibitors (such as axitinib,
everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or
dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical
trials are not available or appropriate.
ee
Cytotoxic chemotherapy has been shown to have minimal efficacy, although
most studies were small and underpowered.
ff
RAI therapy is an option in some patients with bone metastases and RAI-sensitive
disease.
gg
Denosumab and intravenous bisphosphonates can be associated with severe
hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at
increased risk of hypocalcemia. Discontinuing denosumab can cause rebound
atypical vertebral fractures.
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Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Hürthle Cell Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
• For solitary CNS lesions, either neurosurgical resection or stereotactic radiosurgeryj is preferred
or
• For multiple CNS lesions, consider radiotherapy,j including whole brain radiotherapyj or stereotactic radiosurgery,j and/or
resection in select cases
• Consider systemic therapy For progressive and/or symptomatic disease
Preferred Regimens
◊ Lenvatinib (category 1)cc,hh,ii
Other
◊ Sorafenib (category 1) cc,hh,ii
Useful in Certain Circumstances
◊ Cabozantinib if progression after lenvatinib and/or sorafenib
◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors
◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors
◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors
and/or
◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no
satisfactory alternative treatment options
◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other
systemic therapies are not available or appropriatecc,dd,ee,gg
• Best supportive care, see the NCCN Guidelines for Palliative Care
CNS
metastases
TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYdd
j Principles of Radiation and RAI Therapy (THYR-C).
bb Ethanol ablation, cryoablation, RFA, etc.
cc
Kinase inhibitor therapy may not be appropriate for patients with stable or slowly
progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B).
dd Commercially available small‑molecule kinase inhibitors (such as axitinib,
everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or
dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical
trials are not available or appropriate.
ee
Cytotoxic chemotherapy has been shown to have minimal efficacy, although
most studies were small and underpowered.
gg
Denosumab and intravenous bisphosphonates can be associated with severe
hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at
increased risk of hypocalcemia. Discontinuing denosumab can cause rebound
atypical vertebral fractures.
hh
After consultation with neurosurgery and radiation oncology; data on the efficacy
of lenvatinib or sorafenib for patients with brain metastases have not been
established.
ii
TKI therapy should be used with caution in otherwise untreated CNS metastases
due to bleeding risk.
HÜRT‑10
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), All rights reserved. NCCN Guidelines®
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Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Medullary Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
MEDU‑6
RECURRENT OR PERSISTENT
LOCOREGIONAL DISEASE
Locoregional
Recurrent or
Persistent Disease;
Distant Metastases
(MEDU‑7)
s Increasing tumor markers, in the absence of structural disease progression, are not an indication for treatment with systemic therapy.
t Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy in Advanced
Thyroid Carcinoma (THYR‑B).
u Treatment with systemic therapy is not recommended for increasing calcitonin/CEA alone.
v Only health care professionals and pharmacies certified through the vandetanib Risk Evaluation and Mitigation Strategy (REMS) program, a restricted distribution
program, will be able to prescribe and dispense the drug.
w Genomic testing including TMB or RET somatic genotyping in patients who are germline wild-type or germline unknown.
TREATMENT
• Surgical resection is the preferred treatment modality
• EBRT/IMRT can be considered for unresectable disease
or, less commonly, after surgical resection
• Consider systemic therapys for unresectable disease
that is symptomatic or progressing by RECIST criteriat,u
Preferred Regimens
◊ Vandetanibv (category 1)
◊ Cabozantinib (category 1)
◊ Selpercatinib (RET mutation-positive)w
◊ Pralsetinib (RET mutation-positive)w
Useful in Certain Circumstances
◊ Pembrolizumab (TMB-H [≥10 mut/Mb])w
• Disease monitoring
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Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Medullary Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
MEDU‑7
RECURRENT OR PERSISTENT DISEASE
DISTANT METASTASES
Asymptomatic
disease
Symptomatic disease
or
Progressiont
• Systemic therapy or clinical trial
Preferred Regimens
◊ Vandetanib (category 1)x
◊ Cabozantinib (category 1)x
◊ Selpercatinib (RET mutation-positive)w
◊ Pralsetinib (RET mutation-positive)w
Other Recommended Regimens
◊ Consider other small‑molecule kinase inhibitorsy
◊ Dacarbazine (DTIC)‑based chemotherapyz
Useful in Certain Circumstances
◊ Pembrolizumab (TMB-H [≥10 mut/Mb])w
• EBRT/IMRT for local symptoms
• Consider intravenous bisphosphonate or denosumabaa therapy for bone
metastases
• Consider palliative resection, ablation (eg, RFA, embolization,
other regional therapy), or other regional treatment
• Best supportive care, see the NCCN Guidelines for Palliative Care
Progressive disease,
see pathway below
sIncreasing tumor markers, in the absence of structural disease progression, are not an indication for
treatment with systemic therapy.
t Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent
disease. Principles of Kinase Inhibitor Therapy in Advanced Thyroid Carcinoma (THYR‑B).
uTreatment with systemic therapy is not recommended for increasing calcitonin/CEA alone.
v Only health care professionals and pharmacies certified through the vandetanib Risk Evaluation and
Mitigation Strategy (REMS) program, a restricted distribution program, will be able to prescribe and
dispense the drug.
wGenomic testing including TMB or RET somatic genotyping in patients who are germline wild-type or
germline unknown.
xClinical benefit can be seen in both sporadic and familial MTC.
y
While not FDA-approved for treatment of medullary thyroid cancer, other commercially available
small‑molecule kinase inhibitors (such as sorafenib, sunitinib, lenvatinib, or pazopanib) can be
considered if clinical trials or preferred systemic therapy options are not available or appropriate, or if
the patient progresses on preferred systemic therapy options.
zDoxorubicin/streptozocin alternating with fluorouracil/dacarbazine or fluorouracil/dacarbazine
alternating with fluorouracil/streptozocin.
aaDenosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients
with hypoparathyroidism and vitamin D deficiency are at increased risk.
• Disease monitoring
• Consider resection (if possible), ablation (eg, RFA, embolization, other
regional therapy)
• Systemic therapys if not resectable and progressing by RECIST criteriat,u
Preferred Regimens
◊ Vandetanibt,v (category 1)
◊ Cabozantinib (category 1)
◊ Selpercatinib (RET mutation-positive)w
◊ Pralsetinib (RET mutation-positive)w
Useful in Certain Circumstances
◊ Pembrolizumab (TMB-H [≥10 mut/Mb])w
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Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Anaplastic Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
STAGEd
R0/R1 resectione
achieved (usually
as incidentally
discovered, very
small ATC)
Adjuvant EBRT/IMRTf
with radiosensitizing
chemotherapyg when
clinically appropriate
EBRT/IMRTf with chemotherapyg
when clinically appropriate
or
Consider molecularly targeted
neoadjuvant therapyh for borderline
resectable disease when safe to do so
Surgery can be
reconsidered after
neoadjuvant therapy
depending on
response
Stage IVA or IVBa,c
(locoregional
disease)
Total thyroidectomy
with therapeutic lymph
node dissection
Resectable
Unresectablee
a Consider core or open biopsy if FNA is “suspicious” for ATC or is not definitive. Morphologic diagnosis combined with immunohistochemistry is necessary to exclude
other entities such as poorly differentiated thyroid cancer, medullary thyroid cancer, squamous cell carcinoma, and lymphoma.
c Preoperative evaluations need to be completed as quickly as possible and involve integrated decision-making in a multidisciplinary team and with the patient. Consider
referral to multidisciplinary high‑volume center with expertise in treating ATC.
d Staging (ST‑1).
e Resectability for locoregional disease depends on extent of involved structures, potential morbidity, and mortality associated with resection. In most cases, there is no
indication for a debulking surgery. Staging (ST‑1) for definitions of R0/R1/R2.
f Principles of Radiation and RAI Therapy (THYR-C).
g Adjuvant/Radiosensitizing Chemotherapy Regimens for Anaplastic Thyroid Carcinoma (ANAP‑A [1 of 3]).
h Regimens that may be used for neoadjuvant therapy include dabrafenib/trametinib for BRAF V600E mutations; selpercatinib or pralsetinib for RET-fusion positive
tumors; and larotrectinib or entrectinib for patients with NTRK gene fusion-positive tumors.
TREATMENT
Incomplete
(R2 resection)
ANAP‑2
Disease
Monitoring
and Management
(ANAP-3)
EBRT/IMRTf with
chemotherapyg when
clinically appropriate
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Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Anaplastic Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
ANAP‑3
b Molecular testing should include BRAF, NTRK, ALK, RET, MSI, dMMR, and tumor mutational burden.
d Staging (ST‑1).
i Consider dabrafenib/trametinib if BRAF V600E mutation positive (Subbiah V, et al. J Clin Oncol 2018;36:7‑13); larotrectinib or entrectinib if NTRK gene fusion positive
(Drilon A, et al. N Engl J Med 2018;378:731‑739; Doebele RC, et al. Lancet Oncol 2020;21:271-282); selpercatinib or pralsetinib if RET fusion positive (Wirth L,
et al. Presented at the Annual Meeting of the European Society for Medical Oncology in Barcelona, Spain; September 27-October 1, 2019. Oral presentation.); or
pembrolizumab for TMB-H (Marabelle A, et al. Presented at the Annual Meeting of ESMO in Barcelona, Spain; September 30, 2019).
j Consider use of intravenous bisphosphonates or denosumab. Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients
with hypoparathyroidism and vitamin D deficiency are at increased risk.
k Systemic Therapy Regimens for Metastatic Disease (ANAP-A [2 of 3]).
DISEASE MONITORING AND MANAGEMENT
• Cross‑sectional imaging
(CT or MRI with contrast)
of brain, neck, chest,
abdomen, and pelvis
at frequent intervals as
clinically indicated
• Consider FDG PET/CT 3–6
months after initial therapy
• Continued disease
monitoring if no
evidence of disease
(NED)
• Palliative locoregional
radiation therapy
• Local lesion control (eg,
bone,j brain metastases)
• Second‑line systemic
therapyk or clinical trial
• Best supportive
care, see the NCCN
Guidelines for Palliative
Care
Stage IVCd
Aggressive
therapy
Palliative
care
• Total thyroidectomy with therapeutic
lymph node dissection if resectable
(R0/R1)
• Consider tracheostomy
• Locoregional radiation therapy
• Systemic therapy (See ANAP‑A [2 of 3])
• Molecular testing for actionable
mutationsi if not previously doneb
• Consider clinical trial
• Palliative locoregional radiation
therapy
• Local lesion control with surgery or
radiation (eg, bone,j brain metastases)
• Consider tracheostomy
• NCCN Guidelines for Central Nervous
System Cancers
• Best supportive care
METASTATIC
DISEASE
TREATMENT
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![Paclitaxel8
60–90 mg/m² IV
or
135–200 mg/m²
Weekly
Every 3–4 weeks
Doxorubicin8
20 mg/m² IV
or
60–75 mg/m² IV
Weekly
Every 3 weeks
Paclitaxel/carboplatin1 (category 2B)
Paclitaxel 60–100 mg/m2
, carboplatin AUC 2 IV
or
Paclitaxel 135–175 mg/m2
, carboplatin AUC 5–6 IV
Weekly
Every 3–4 weeks
Docetaxel/doxorubicin1 (category 2B)
Docetaxel 60 mg/m2
IV, doxorubicin 60 mg/m2
IV (with pegfilgrastim)
or
Docetaxel 20 mg/m2
IV, doxorubicin 20 mg/m2
IV
Every 3–4 weeks
Weekly
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Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Version 3.2022
Thyroid Carcinoma – Anaplastic Carcinoma
NCCN Guidelines Index
Table of Contents
Discussion
ANAP‑A
2 OF 3
SYSTEMIC THERAPY
Systemic Therapy Regimens for Metastatic Disease
Preferred Regimens
Dabrafenib/trametinib2
(BRAF V600E mutation positive)
Dabrafenib 150 mg PO
and
Trametinib 2 mg PO
Twice daily
Once daily
Larotrectinib3
(NTRK gene fusion positive) 100 mg PO Twice daily
Entrectinib4
(NTRK gene fusion positive) 600 mg PO Once daily
Pralsetinib5
(RET fusion positive) 400 mg PO Once daily
Selpercatinib6
(RET fusion positive)
120 mg PO (50 kg)
or
160 mg PO (≥50 kg)
Twice daily
Other Recommended Regimens
Useful in Certain Circumstances
Doxorubicin/cisplatin8 Doxorubicin 60 mg/m² IV, cisplatin 40 mg/m² IV Every 3 weeks
Pembrolizumab7
(TMB-H [≥10 mut/Mb])
200 mg IV
or
400 mg IV
Every 3 weeks
Every 6 weeks
References
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![NCCN Guidelines Version 3.2022
Thyroid Carcinoma
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(NCCN®
), All rights reserved. NCCN Guidelines®
and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN Guidelines Index
Table of Contents
Discussion
THYR‑C
2 OF 5
PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY
IODINE-131 ADMINISTRATION
Administered Activity
See special circumstances below for pediatric dose adjustment.
• Remnant ablation:
30–50 mCi
◊ If RAI ablation is used in T1b/T2 (1–4 cm), clinical N0 disease, in
the absence of other adverse pathologic, laboratory, or imaging
features, 30–50 mCi of iodine-131 is recommended (category 1)
following either thyrotropin alfa stimulation or thyroid hormone
withdrawal. This dose of 30–50 mCi may also be considered
(category 2B) for patients with T1b/T2 (1–4 cm) with small-
volume N1a disease (fewer than 5 lymph node metastases 2
mm in diameter) and for patients with primary tumors 4 cm,
clinical M0 with minor extrathyroidal extension.4,5
• Adjuvant therapy:
50–150 mCi
◊ For higher likelihood of residual disease based on operative
pathology or pretherapy radioiodine scan
• Treatment of known disease
100–200 mCi
◊ For proven unresectable or metastatic disease based on
pathology or pretherapy radioiodine scan
Dosimetry can be used to determine maximal dose at high-volume
centers for documented nonresectable, large-volume, iodine-
concentrating, residual, or recurrent disease. Generally, the
maximum 48-hour whole-body dose should not exceed ~80 mCi to
avoid pulmonary fibrosis in the case of diffuse lung metastases,
and the bone marrow retention maximum should not exceed ~120
mCi at 48 hours.1
Special Circumstances
• Pediatric patients:
Chest imaging using non-contrast CT prior to treatment to assess
for lung metastases
Weight-based dose adjustment for pediatric patients assuming
routine dosing for 70 kg adult (ie, a 150 mCi dose for a 70 kg adult
would translate to 2.15 mCi/kg for the pediatric patient)6
Special Circumstances
• RAI after imaging study or procedure using iodine contrast agent:
Wait 2 months to allow for free iodine levels to decrease (100
mcg/24 hours) and allow for optimal RAI uptake7,8
Consider measurement of 24-hour urine iodine to confirm a normal
free iodine prior to preparing for dosing.
• Breastfeeding patients:
Wait 3–6 months after cessation of lactation or with normalization
of serum prolactin levels.
Complete cessation of breastfeeding after iodine-123 or iodine-131
administration for the current infant. There should be no increased
risk to mother or infant for breastfeeding with subsequent births
assuming no radioiodine is administered around the subsequent
birth/breastfeeding period.9
• Decreased glomerular filtration rate (GFR)/end-stage renal disease
(ESRD)/hemodialysis:
Special consideration to administered dose, and timing with
respect to dialysis to maximize therapeutic effect and minimize
non-thyroid uptake/exposure10
Multidisciplinary involvement including close monitoring by
radiation safety to coordinate administration, monitoring, and
minimization of exposure to others
• Patients desiring pregnancy
Patients should be counseled to wait at least 6 months after
iodine-131 therapy to attempt pregnancy to avoid adverse
pregnancy outcomes (such as fetal hypothyroidism, malformation,
increased malignancy risk in the child, or fetal demise [with
high doses]) related to RAI. For many patients a longer interval
before attempting pregnancy may be recommended to confirm
disease-free status at 6–12 months post-RAI. In these cases,
earlier pregnancy is inadvisable as it would interfere with disease
detection and further management.
In selective cases when doses are high or other considerations
are present, integrating care with reproductive endocrinology/
oncofertility for men and women may be appropriate.
References
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NCCN Guidelines Version 3.2022
Thyroid Carcinoma
MS-5
System for Reporting Thyroid Cytopathology.61
As of the 2021 update to
the NCCN Guidelines for Thyroid Carcinoma, management
recommendations are no longer provided for nodules classified as
Bethesda I and Bethesda II. Pathology and cytopathology slides should be
reviewed at the treating institution by a pathologist with expertise in the
diagnosis of thyroid disorders. Although FNA is a very sensitive test—
particularly for papillary carcinoma—false-negative results are sometimes
obtained; therefore, a reassuring FNA should not override worrisome
clinical or radiographic findings.62,63
Molecular diagnostic testing to detect individual mutations (eg, BRAF
V600E, RET/PTC, RAS, PAX8/PPAR [peroxisome proliferator-activated
receptor] gamma) or pattern recognition approaches using molecular
classifiers may be useful in the evaluation of FNA samples that are
indeterminate to assist in management decisions.64-72
The BRAF V600E
mutation occurs in about 45% of patients with papillary carcinoma and is
the most common mutation.73
Some studies have linked the BRAF V600E
mutation to poor prognosis, especially when occurring with TERT
promoter mutation.74-77
The choice of the precise molecular test depends
on the cytology and the clinical question being asked.78-81
Indeterminate
groups include: 1) follicular or Hürthle cell neoplasms (Bethesda IV); and
2) AUS/FLUS (Bethesda III).82-84
The NCCN Panel recommends
consideration of molecular diagnostic testing for these indeterminate
groups.85,86
Historically, studies have shown that molecular diagnostics do not perform
well for Hürthle cell neoplasms.83,87,88
More recently, modern genomic
classifiers have shown promise for diagnosis of Hürthle cell-containing
specimens, with sensitivity values ranging from 88.9% to 92.9% and
specificity values ranging from 58.8% to 69.3% for detecting Hürthle cell
cancers.89,90
Molecular diagnostic testing may include multigene assays or
individual mutational analysis. In addition to their utility in diagnostics,
molecular markers are beneficial for making decisions about targeted
therapy options for advanced disease and for informing eligibility for some
clinical trials. In addition, the presence of some mutations may have
prognostic importance.
A minority of panelists expressed concern regarding active nodule
surveillance of follicular lesions because they were perceived as
potentially pre-malignant lesions with a very low, but unknown, malignant
potential if not surgically resected (leading to recommendations for either
nodule surveillance or considering lobectomy in lesions classified as
benign by molecular testing). Clinical risk factors, sonographic patterns,
and patient preference can help determine whether nodule surveillance or
surgery is appropriate for these patients. Guidance regarding nodule
surveillance from the ATA and the ACR TI-RADS should be followed.3,59
A
systematic review including 27 studies that evaluated repeat FNA in
AUS/FLUS nodules showed that 48% (95% CI, 43%–54%) of nodules
were reclassified as benign, with a negative predictive value (NPV) greater
than 96%.91
FNA may be repeated for AUS/FLUS, especially if molecular
diagnostics are technically inadequate.
Rather than proceeding to immediate surgical resection to obtain a
definitive diagnosis for these indeterminate FNA cytology groups (follicular
lesions), patients can be followed with nodule surveillance if the
application of a specific molecular diagnostic test (in conjunction with
clinical and ultrasound features) results in a predicted risk of malignancy
that is comparable to the rate seen in cytologically benign thyroid FNAs
(approximately ≤5%). It is important to note that the predictive value of
molecular diagnostics may be significantly influenced by the pre-test
probability of disease associated with the various FNA cytology groups.
Furthermore, in the cytologically indeterminate groups, the risk of
malignancy from FNA can vary widely between institutions.61,92
Because
the published studies have focused primarily on adult patients with thyroid
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NCCN Guidelines Version 3.2022
Thyroid Carcinoma
MS-8
with thyroid carcinoma—especially those who are older than 40 years—
may be regarded with special concern.121
Familial Syndromes
Familial, non-medullary carcinoma accounts for about 5% of PTCs and, in
some cases, may be clinically more aggressive than the sporadic
form.122,123
For patients to be considered as having familial papillary
carcinoma, most studies require at least three first-degree relatives to be
diagnosed with papillary carcinoma because the finding of cancer in a
single first-degree relative may just be a chance event. Microscopic
familial papillary carcinoma tends to be multifocal and bilateral, often with
vascular invasion, lymph node metastases, and high rates of recurrence
and distant metastases.124
Other familial syndromes associated with
papillary carcinoma are familial adenomatous polyposis,125
Carney
complex (multiple neoplasia and lentiginosis syndrome, which affects
endocrine glands),126
and Cowden syndrome (multiple hamartomas).127
The prognosis for patients with all of these syndromes is not different from
the prognosis of those with spontaneously occurring papillary carcinoma.
Tumor Variables Affecting Prognosis
Some tumor features have a profound influence on prognosis.111,128-130
The
most important features are tumor histology, primary tumor size, local
invasion, necrosis, vascular invasion, BRAF V600E mutation status, and
metastases.74,131,132
For example, vascular invasion (even within the
thyroid gland) is associated with more aggressive disease and with a
higher incidence of recurrence.133-136
The CAP protocol provides
definitions of vascular invasion and other terms (see Protocol for the
Examination of Specimens From Patients With Carcinomas of the Thyroid
Gland on the CAP website).96
In patients with sporadic medullary
carcinoma, a somatic RET oncogene mutation confers an adverse
prognosis.137
A meta-analysis including 13 studies showed that PD-L1
expression is associated with lower disease-free survival (DFS) (hazard
ratio [HR], 3.37; 95% CI, 2.54–4.48; P .00001) and overall survival (OS)
(HR, 2.52; 95% CI, 1.20–5.32; P = .01) in patients with thyroid cancer.138
Another meta-analysis including 15 studies also showed a significant
association between PD-L1 expression and lower DFS (HR, 1.90; 95% CI,
1.33–2.70; P .001), but OS was not significantly associated with PD-L1
expression.139
Subgroup analyses showed that the association between
PD-L1 expression and DFS was significant for papillary carcinoma (HR,
2.18; 95% CI, 1.08–4.39), but not for poorly differentiated or anaplastic
thyroid carcinoma (HR, 1.63; 95% CI, 0.62–4.32).
Histology
Although survival rates with typical papillary carcinoma are quite good,
cancer-specific mortality rates vary considerably with certain histologic
subsets of tumors.1
A well-defined tumor capsule, which is found in about
10% of PTCs, is a particularly favorable prognostic indicator. A worse
prognosis is associated with anaplastic tumor transformation; tall-cell
papillary variants, which have a 10-year mortality of up to 25%; columnar
variant papillary carcinoma (a rapidly growing tumor with a high mortality
rate); hobnail variant papillary carcinoma, which is associated with
increased rates of local and distant metastasis; and diffuse sclerosing
variants, which infiltrate the entire gland.37,140-142
NIFTP, formerly known as noninvasive encapsulated follicular variant of
papillary thyroid carcinoma (EFVPTC), is characterized by its follicular
growth pattern, encapsulation or clear demarcation of the tumor from
adjacent tissue with no invasion, and nuclear features of papillary
carcinoma.143,144
NIFTP tumors have a low risk for adverse outcomes and,
therefore, require less aggressive treatment.144-148
NIFTP was re-classified
in 2016 to prevent overtreatment of this indolent tumor type as well as the
psychological consequences of a cancer diagnosis on the patient.143,144
A
systematic review including 29 studies showed that the pooled prevalence
rates of NIFTP within EFVPTC and PTC were 43.5% (95% CI, 33.5%–
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MS-13
However, some prominent thyroid cancer specialists (including some at
NCCN Member Institutions) oppose this view and advocate unilateral
lobectomy for most patients with papillary and follicular carcinoma based
on 1) the low mortality among most patients (ie, those patients categorized
as low risk by the AMES and other prognostic classification schemes); and
2) the high complication rates reported with more extensive
thyroidectomy.117,191,207
The large thyroid remnant remaining after
unilateral lobectomy, however, may complicate long-term follow-up with
serum Tg determinations and whole body iodine-131 imaging. Panel
members recommend total lobectomy (without RAI ablation) for patients
with papillary carcinoma who have incidental small-volume pathologic N1A
metastases (5 involved nodes with no metastasis 5 mm, in largest
dimension).208
NCCN Panel Members believe that lobectomy alone is adequate
treatment for papillary microcarcinomas provided the patient has not been
exposed to radiation, has no other risk factors, and has a tumor 1 cm or
smaller that is unifocal and confined to the thyroid without vascular
invasion (see Primary Treatment in the NCCN Guidelines for Papillary
[Thyroid] Carcinoma).3,209-212
Total lobectomy alone is also adequate
treatment for NIFTP pathologies (see Tumor Variables Affecting
Prognosis, Histology) and minimally invasive follicular thyroid carcinomas
(see Primary Treatment in the NCCN Guidelines for Follicular [Thyroid]
Carcinoma). However, completion thyroidectomy is recommended for any
of the following: tumor larger than 4 cm in diameter, positive resection
margins, gross extrathyroidal extension, macroscopic multifocal disease
(ie, 1 cm), macroscopic nodal metastases, confirmed contralateral
disease, or vascular invasion.3
Note that “gross extrathyroidal extension”
refers to spread of the primary tumor outside of the thyroid capsule with
invasion into the surrounding structures such as strap muscles, trachea,
larynx, vasculature, esophagus, and/or recurrent laryngeal nerve.131,213,214
Completion Thyroidectomy
This procedure is recommended when remnant ablation is anticipated or if
long-term follow-up is planned with serum Tg determinations and with (or
without) whole body iodine-131 imaging. Large thyroid remnants are
difficult to ablate with iodine-131.206
Completion thyroidectomy has a
complication rate similar to that of total thyroidectomy. Some experts
recommend completion thyroidectomy for routine treatment of tumors 1
cm or larger, because approximately 50% of patients with cancers of this
size have additional cancer in the contralateral thyroid lobe.174,215-221
In
patients with local or distant tumor recurrence after lobectomy, cancer is
found in more than 60% of the resected contralateral lobes.218
Miccoli et al studied irradiated children from Chernobyl who developed
thyroid carcinoma and were treated by lobectomy; they found that 61%
had unrecognized lung or lymph node metastases that could only be
identified after completion thyroidectomy.120
In another study, patients who
underwent completion thyroidectomy within 6 months of their primary
operation developed significantly fewer lymph node and hematogenous
recurrences, and they survived significantly longer than did those in whom
the second operation was delayed for more than 6 months.219
Surgical Complications
The most common significant complications of thyroidectomy are
hypoparathyroidism and recurrent laryngeal nerve injury, which occur
more frequently after total thyroidectomy.222
Transient clinical
hypoparathyroidism postoperatively is common in adults223
and
children120,224
undergoing total thyroidectomy. The rates of long-term
recurrent laryngeal nerve injury and hypoparathyroidism, respectively,
were 3% and 2.6% after total thyroidectomy and 1.9% and 0.2% after
subtotal thyroidectomy.225
One study reported hypocalcemia in 5.4% of
patients immediately after total thyroidectomy, persisting in only 0.5% of
patients 1 year later.226
Another study reported a 3.4% incidence of
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long-term recurrent laryngeal nerve injury and a 1.1% incidence of
permanent hypocalcemia.227
When experienced surgeons perform
thyroidectomies, complications occur at a lower rate. A study of 5860
patients found that surgeons who performed more than 100
thyroidectomies a year had the lowest overall complication rate (4.3%),
whereas surgeons who performed fewer than 10 thyroidectomies a year
had four times as many complications.228
Radioactive Iodine—Diagnostics and Treatment
Diagnostic Whole Body Imaging and Thyroid Stunning
When indicated, diagnostic whole body iodine-131 imaging is
recommended after surgery to assess the completeness of thyroidectomy
and to assess whether residual disease is present (see RAI Being
Considered Based on Clinicopathologic Features in the NCCN Guidelines
for Papillary, Follicular, and Hürthle Cell Carcinoma). However, a
phenomenon termed “stunning” may occur when imaging doses of iodine-
131 induce follicular cell damage.229
Stunning decreases uptake in the
thyroid remnant or metastases, thus impairing the therapeutic efficacy of
subsequent iodine-131.230
To avoid or reduce the stunning effect, the
following have been suggested: 1) the use of small doses of iodine-131
(1–2 mCi) or iodine-123 (2–4 mCi); and/or 2) a shortened interval (48–72
hours) between the diagnostic iodine-131 dose and the therapeutic dose.
Iodine-123 is more expensive, and smaller iodine-131 doses have reduced
sensitivity when compared with larger iodine-131 doses.229-231
In addition,
a large thyroid remnant may obscure detection of residual disease with
iodine-131 imaging. Some experts recommend that diagnostic iodine-131
imaging be avoided completely with decisions based on the combination
of tumor stage and serum Tg.229
Other experts advocate that whole body
iodine-131 diagnostic imaging may alter therapy, for example: 1) when
unsuspected metastases are identified; or 2) when an unexpectedly large
remnant is identified that requires additional surgery or a reduction in RAI
dosage to avoid substantial radiation thyroiditis.3,229,232,233
If iodine contrast
agent was used with imaging, then RAI should not begin for at least 2
months after the procedure in order to allow for free iodine levels to
decrease and thus allow for optimal RAI uptake.234,235
Note that diagnostic imaging is used less often for patients at low risk. A
false-negative pretreatment scan is possible and should not prevent use of
RAI if otherwise indicated (see Eligibility for Postoperative Radioactive
Iodine [RAI] in this Discussion, below). For known or suspected distant
metastatic disease, diagnostic whole body iodine-123 or iodine-131
imaging before postoperative RAI may be considered.
Eligibility for Postoperative Radioactive Iodine (RAI)
The NCCN Panel recommends a selective use approach to postoperative
RAI administration. The three general, but overlapping, functions of
postoperative RAI administration include: 1) ablation of the normal thyroid
remnant, which may help in surveillance for recurrent disease (see below);
2) adjuvant therapy to try to eliminate suspected micrometastases; or 3)
RAI therapy to treat known persistent disease. The NCCN Guidelines
have three different pathways for postoperative RAI administration based
on clinicopathologic factors: 1) RAI typically recommended; 2) RAI
selectively recommended; and 3) RAI not typically recommended (see
Clinicopathologic Factors in the NCCN Guidelines for Papillary, Follicular,
and Hürthle Cell Carcinoma).
Postoperative RAI is typically recommended for patients at high risk of
having persistent disease remaining after total thyroidectomy and includes
patients with any of the following factors: 1) gross extrathyroidal extension;
2) a primary tumor greater than 4 cm; 3) postoperative unstimulated Tg
greater than 10 ng/mL; or 4) 6 or more positive lymph nodes or bulky
lymph nodes. In the case of follicular or Hürthle cell carcinoma, extensive
vascular invasion (≥4 foci) is another indication for postoperative RAI.
Postoperative RAI is also frequently recommended for patients with
known/suspected distant metastases at presentation (see
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Therefore, in patients at low and intermediate risk, the clinical benefit of
routine remnant ablation as a requirement for optimal follow-up remains
uncertain.
Thyroid hormone withdrawal may be recommended to increase uptake
from RAI treatment.250
Duration of time off thyroid hormone depends on
the extent of thyroidectomy and approach to hormone replacement in the
initial postoperative setting. Two retrospective studies showed that
patients with distantly metastatic RAI-avid differentiated thyroid cancer
who received recombinant human TSH in preparation for RAI treatment
did not differ significantly in treatment response or survival, compared to
patients who received RAI treatment after thyroid hormone
withdrawal.251,252
However, thyroid hormone withdrawal continues to be
preferred by the NCCN Panel for preparation of RAI treatment compared
to thyrotropin alfa, due to an increased likelihood of augmentation of the
delivered radiation dose. Guidance for preparing the patient and managing
iodine-131 administration can be found in the Principles of Radiation and
Radioactive Iodine Therapy: Iodine-131 Administration in the NCCN
Guidelines for Thyroid Carcinoma.
Data suggest that lower doses of RAI are as effective as higher doses—30
versus 100 mCi—for ablation in patients with low-risk thyroid cancer (eg,
T1b/T2 [1–4 cm], clinical N0 disease).35,36,253
The NCCN Guidelines reflect
a more cautious approach to using RAI ablation based on these
randomized trials.254
If RAI ablation is used, the NCCN Guidelines
recommend (category 1) 30 mCi of iodine-131 for RAI ablation in patients
at low risk based on these randomized trials. This same ablation dose—30
mCi—may be considered (category 2B) in patients at slightly higher risk.255
RAI ablation is not recommended in patients at very low risk.
RAI therapy for thyroid cancer carries the risk of possible adverse effects
including salivary gland dysfunction, lacrimal gland dysfunction, transient
gonadal dysfunction, and secondary primary malignancies.256
The possible
benefits of RAI should be weighed with the risk of adverse effects as part
of treatment decision-making.254
Adverse effects may be minimized by
using lower doses of RAI.35
Historically, the three methods of determining iodine-131 therapy activities
(doses) have included: empiric fixed doses, quantitative dosimetry, and
upper-bound limits that are set by blood dosimetry.3,229,257,258
Most patients
at NCCN Member Institutions receive postoperative RAI based on empiric
fixed dosing; a few centers use a combination of blood dosimetry and
quantitative lesional dosimetry. In the past, hospitalization was required to
administer therapeutic doses of iodine-131 greater than 30 mCi (1110
MBq). However, hospitalization is no longer necessary in most states,
because a change in federal regulations permits the use of much larger
iodine-131 doses in patients who are ambulatory.257
However, iodine-131
therapy with high doses (200 mCi) is best done in medical centers with
experience using high doses. Dosimetry can be used to determine the
maximal safe dose for treatment of unresectable, large-volume, iodine-
concentrating, residual, or recurrent disease.
Administration of a fixed dose of iodine-131 is the most widely used and
simplest method. Most clinics use this method regardless of the
percentage uptake of iodine-131 in the remnant or metastatic lesion.
Patients with uptake in tumor are routinely treated with large, fixed
amounts of iodine-131. Lymph node metastases may be treated with
about 100 to 175 mCi (3700–6475 MBq) of iodine-131. Cancer growing
through the thyroid capsule (and incompletely resected) is treated with 150
to 200 mCi (5550–7400 MBq). Patients with distant metastases are
usually treated with 100 to 200 mCi (3700–7400 MBq) of iodine-131,
which typically will not induce radiation sickness or produce serious
damage to other structures but may exceed generally accepted safety
limits to the blood in the elderly and in those with impaired kidney
function.259,260
Diffuse pulmonary metastases that concentrate 50% or
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alfa is well tolerated; nausea (10.5%) and transient mild headache (7.3%)
are its main adverse effects.265
It is associated with significantly fewer
symptoms and dysphoric mood states than hypothyroidism induced by
thyroid hormone withdrawal.269
An international study was performed to assess the effects of two rhTSH
dosing schedules on whole body iodine-131 imaging and serum Tg levels
when compared with imaging and Tg levels obtained after thyroid
hormone withdrawal.265
Data showed that the combination of rhTSH–
stimulated whole body imaging and serum Tg measurements detected
100% of metastatic carcinoma.265
In this study, 0.9 mg of rhTSH was given
intramuscularly every day for 2 days, followed by a minimum of 4 mCi of
iodine-131 on the third day. Whole body imaging and Tg measurements
were performed on the fifth day. Whole body iodine-131 images were
acquired after 30 minutes of imaging or after obtaining 140,000 counts,
whichever came first. A serum Tg of 2.0 ng/mL or higher, obtained 72
hours after the last rhTSH injection, indicates that thyroid tissue or thyroid
carcinoma is present, regardless of the whole body imaging findings.265,270
Measuring Serum Tg and Anti-Tg Antibodies
Serum Tg measurement is the best means of detecting thyroid tissue,
including carcinoma. Tg can be measured when TSH has been
stimulated—either by thyroid hormone withdrawal or by thyrotropin alfa—
because in this setting, serum Tg has a lower false-negative rate than
whole body iodine-131 imaging.264,265,268,271
Serum Tg levels vary in
response to the increase in serum TSH after thyroid hormone withdrawal
or TSH stimulation. Serum Tg generally does not increase as much after
thyrotropin alfa as after withdrawal of thyroid hormone. The conditions for
TSH–stimulated, whole body iodine-131 imaging stipulate using 4-mCi
iodine-131 doses (based on the trial)265
and an imaging time of 30 minutes
or until 140,000 counts are obtained. Tg measurements may also be
obtained without stimulating TSH using ultrasensitive assays (ie, second-
generation Tg immunometric assays [TgIMAs]).267,272
Evaluation of serum
Tg and anti-Tg antibody levels is helpful for the purpose of obtaining a
postoperative baseline.
Functional sensitivity less than or equal to 0.1 ng/mL for Tg and 0.9 ng/mL
for TgAb are reported for newer generation assays, compared to 1.0
ng/mL for Tg and 20 ng/mL for TgAb for older generation assays.266,267
With the availability of next-generation assays, it is now widely accepted
that stimulated Tg is no longer necessary. Anti-Tg antibodies should be
measured in the same serum sample taken for Tg assay, because these
antibodies (which are found in ≤25% of patients with thyroid carcinoma)
invalidate serum Tg measurements in most assays.272-274
These antibodies
typically falsely lower the Tg value in immunochemiluminometric assays
(ICMAs) and immunoradiometric assays (IRMAs), while raising the value
in older radioimmunoassays. Although the clinical importance of anti-Tg
antibodies is unclear, their persistence for more than 1 year after
thyroidectomy and RAI ablation probably indicates the presence of
residual thyroid tissue and possibly an increased risk of recurrence.274
In one study, 49% of patients had a recurrence if they had undetectable
serum Tg and serum anti-Tg antibody levels of 100 units/mL or more when
compared with only 3% of patients with undetectable serum Tg and serum
anti-Tg antibodies of less than 100 units/mL.275
In patients with coexistent
autoimmune thyroid disease at the time of surgery, anti-Tg antibodies may
persist for far longer. In a study of 116 patients with anti-Tg antibodies
before thyroidectomy, antibodies remained detectable for up to 20 years in
some patients without detectable thyroid tissue, and the median time to
disappearance of antibodies was 3 years.276
Patients with persistently
undetectable serum Tg and anti-Tg antibody levels have longer DFS when
compared with patients who have detectable levels.277
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Treating Patients with Positive Tg and Negative Imaging
Post-treatment iodine-131 imaging may indicate the location of
metastases when the serum Tg level is increased, but a tumor [or
metastases] cannot be found by physical examination or other localizing
techniques such as diagnostic iodine-131 imaging, neck ultrasonography,
CT, MRI, or PET. Pulmonary metastases may be found only after
administering therapeutic doses of iodine-131 and obtaining whole body
imaging within a few days of treatment.278
In a study of 283 patients
treated with 100 mCi (3700 MBq) of iodine-131, 6.4% had lung and bone
metastases detected after treatment that had been suspected based on
high serum Tg concentrations alone but that had not been detected after
2-mCi (74 MBq) diagnostic imaging.279
Unfortunately, most patients who are diagnostic imaging–negative and
Tg-positive are not rendered disease free by iodine-131 therapy; however,
the tumor burden may be diminished.280
Thus, most patients with residual
or recurrent disease confined to the neck undergo reoperation rather than
RAI therapy in the hopes of a cure. RAI therapy is more commonly
considered for those with distant metastases or inoperable local disease.
Patients not benefiting from this therapy can be considered for clinical
trials, especially those patients with progressive metastatic disease. When
a large tumor is not visible on diagnostic whole body imaging, its ability to
concentrate iodine-131 is very low; thus, the tumor will not respond to
iodine-131 therapy.
Thyroid Hormone Suppression of TSH
The use of postoperative levothyroxine to decrease TSH levels is
considered optimal in treatment of patients with papillary, follicular, or
Hürthle cell carcinoma, because TSH is a trophic hormone that can
stimulate the growth of cells derived from thyroid follicular epithelium.246,281-
283
However, the optimal serum levels of TSH have not been defined
because of a lack of specific data; therefore, the NCCN Panel
recommends tailoring the degree of TSH suppression to the risk of
recurrence and death from thyroid cancer for each individual patient. For
patients with known residual carcinoma or those at high risk for
recurrence, the recommended TSH level is below 0.1 mU/L. For patients
at low risk and for those patients with an excellent response to initial
therapy who are in remission, the recommended TSH level is either
slightly below or slightly above the lower limit of the reference range (0.5–
2 mU/L). The risks and benefits of TSH-suppressive therapy must be
balanced for each individual patient because of the potential toxicities
associated with TSH-suppressive doses of levothyroxine, including cardiac
tachyarrhythmias (especially in the elderly), bone demineralization
(particularly in post-menopausal women), and frank symptoms of
thyrotoxicosis.3,284,285
An adequate daily intake of calcium (1200 mg/day)
and vitamin D (1000 units/day) is recommended for patients whose TSH
levels are chronically suppressed. However, reports do not suggest that
bone mineral density is altered in patients receiving levothyroxine.286,287
Decreased recurrence and cancer-specific mortality rates for differentiated
thyroid carcinoma have been reported for patients treated with thyroid
hormone suppressive therapy.12,240,243,283,288-290
The average dosage
needed to attain serum TSH levels in the euthyroid range is higher in
patients who have been treated for thyroid carcinoma (2.11 mcg/kg per
day) than in those patients with spontaneously occurring primary
hypothyroidism (1.62 mcg/kg per day).290
Even higher doses are required
to suppress serum TSH in patients who have been treated for thyroid
carcinoma. The optimal TSH level to be achieved is uncertain in patients
who have been treated for thyroid carcinoma. Superior outcomes were
associated with aggressive thyroid hormone suppression therapy in
patients at high risk but were achieved with modest suppression in
patients with stage II disease.243
Excessive TSH suppression (into the
undetectable, thyrotoxic range) is not required to prevent disease
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MS-21
disease.309
Novel treatments for patients with metastatic differentiated
thyroid carcinoma have been evaluated.310-317
Agents include multitargeted
kinase inhibitors, such as lenvatinib,310,313,318-325
sorafenib,326-333
sunitinib,331,334,335
axitinib,336-338
everolimus,339,340
vandetanib,341
cabozantinib,311,342
and pazopanib343
; BRAF V600E mutant inhibitors, such
as vemurafenib or dabrafenib344-347
; tropomyosin receptor kinase (TRK)
inhibitors, such as larotrectinib or entrectinib348,349
; RET inhibitors such as
selpercatinib or pralsetinib350,351
; and anti-PD-1 antibodies such as
pembrolizumab.352
Data suggest that anaplastic lymphoma kinase (ALK)
inhibitors may be effective in patients with papillary carcinoma who have
ALK gene fusion.353-356
Clinical trials suggest that kinase inhibitors have a clinical benefit (partial
response rates plus stable disease) in 50% to 60% of subjects, usually for
about 12 to 24 months.313,321,331,343,357-359
Lenvatinib is the preferred
systemic therapy option for the treatment of patients with RAI-refractory
differentiated thyroid cancer (see Papillary Thyroid Carcinoma in this
Discussion and the NCCN Guidelines for Papillary [Thyroid] Carcinoma).
Vandetanib and cabozantinib, oral kinase inhibitors, are preferred
systemic therapy options for the treatment of medullary carcinoma in
patients with unresectable locally advanced or metastatic disease, and
RET inhibitors (selpercatinib and pralsetinib) are preferred options for RET
mutation-positive disease (see Medullary Thyroid Carcinoma in this
Discussion and the NCCN Guidelines for Medullary [Thyroid] Carcinoma).
Cabozantinib is also an option for RAI-refractory differentiated thyroid
carcinoma that has progressed on VEGFR-targeted therapies such as
lenvatinib and sorafenib.360
Severe or fatal side effects from kinase
inhibitors include bleeding, hypertension, stroke, and liver toxicity;
however, most side effects can be managed and are reversible with
discontinuation of the drug.320,321,361-366
Dose modifications of kinase
inhibitors may be required. Pazopanib has been reported to cause
reversible hypopigmentation.367
Papillary Thyroid Carcinoma
Surgical Therapy
Imaging is performed before surgery to ascertain the extent of disease and
to aid in the surgical decision-making process. A cervical ultrasound,
including the thyroid and the central and lateral compartments, is the
recommended principal imaging modality.368
In one report, cervical
ultrasound performed before primary surgery for newly diagnosed thyroid
cancer identified metastatic sites not appreciated on physical examination
in 20% of patients, and surgical strategy was altered in 39% of patients.369
Surgeon-performed preoperative ultrasound identified nonpalpable
metastatic lymph nodes in 24% of patients.370
In more than 700 patients
with PTC, preoperative ultrasound detected nonpalpable nodal
metastases in 33% of subjects.371
Preoperative ultrasound findings altered
the operation in more than 40% of cases. In another report,372
operative
management was altered in 23% of the total group due to findings on the
preoperative ultrasound. These studies indicate that preoperative
ultrasound has a high sensitivity for nodal disease and will detect
nonpalpable nodal metastases in 20% to 33% of patients, and ultrasound
should alter the index operation in a similar percentage of patients. In most
cases, lesions suspicious for locoregional recurrence, which are amenable
to needle biopsy, should be interrogated with FNA biopsy before surgery.
Tg washout assay is a useful adjunct to FNA biopsy in these cases,
particularly if cytology is negative. Cross-sectional imaging (CT or MRI)
should be performed for locally advanced disease (eg, if the thyroid lesion
is fixed, bulky, or substernal) or for vocal cord paresis. Iodinated contrast
is required for optimal cervical imaging with CT, although iodinated
contrast will delay treatment with RAI; delaying RAI treatment is not
harmful. Assessment of vocal cord mobility is recommended for patients
with abnormal voice, a surgical history involving the recurrent laryngeal or
vagus nerves, invasive disease, or bulky disease of the central neck.
Evaluation is essential in patients with voice changes. Vocal cord mobility
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NCCN Guidelines Version 3.2022
Thyroid Carcinoma
MS-22
may be evaluated by ultrasound, mirror indirect laryngoscopy, or fiber-
optic laryngoscopy.373
The NCCN Panel agreed on the characteristics of patients at higher risk
who require total thyroidectomy as the primary treatment (see
Preoperative or Intraoperative Decision-Making Criteria in the NCCN
Guidelines for Papillary [Thyroid] Carcinoma).3,374,375
A total thyroidectomy
is recommended for patients with any one of the following factors,
including: known distant metastases, extrathyroidal extension, tumor
larger than 4 cm in diameter, lateral cervical lymph node metastases or
gross central neck lymph node metastases, or poorly differentiated
histology. Total thyroidectomy may be considered for patients with bilateral
nodularity or a prior exposure to radiation (category 2B for radiation
exposure). Clinically positive and/or biopsy-proven nodal metastases
should be treated with a formal compartmental resection. In the central
neck, this is achieved through a unilateral or bilateral level VI dissection. In
the lateral compartment, a formal modified radical neck dissection
including levels II, III, IV, and Vb should be performed.376
Extending the
dissection field into levels I or Va may be necessary when these levels are
clinically involved. Based on the results of two randomized controlled
trials, the panel does not recommend prophylactic central neck dissection
if the cervical lymph nodes are clinically negative. Two trials of randomized
patients with cN0 PTC to receive either total thyroidectomy alone or total
thyroidectomy plus central neck dissection showed no difference in
outcomes between the two groups.377,378
Central neck dissection will be
required ipsilateral to a modified radical neck dissection done for clinically
involved lateral neck lymph nodes in most cases. Selective dissection of
individual nodal metastases (ie, cherry picking) is not considered adequate
surgery for nodal disease in a previously undissected field.
The NCCN Panel did not uniformly agree about the preferred primary
surgery for patients with PTC who are assumed to be at lower risk of
cancer-specific mortality. As previously mentioned, the extent of thyroid
resection—ipsilateral lobectomy versus total thyroidectomy—is very
controversial for lower-risk PTC, and lobectomy is preferred for these
patients, while total thyroidectomy is a category 2B option (see Ipsilateral
Lobectomy Versus Total Thyroidectomy in this Discussion). Lobectomy
plus isthmusectomy is recommended for patients who cannot (or refuse
to) take thyroid hormone replacement therapy for the remainder of their
lives.222
Note that some patients prefer to have total thyroidectomy to
avoid having a second surgery (ie, completion thyroidectomy). Other
patients prefer to have a lobectomy in an attempt to avoid thyroid hormone
replacement therapy. Most guidelines (eg, NCCN, ATA3
) do not
recommend active surveillance for patients with PTC. However, for PTC 1
cm or smaller and no concerning lymph node involvement or risk features
(eg, posterior location, abutting the trachea or apparent invasion), surgery
may not be warranted, and active surveillance with ultrasound may be
sufficient.379-382
A study of more than 5000 patients found that survival of patients after
partial thyroidectomy was similar to the survival after total thyroidectomy
for patients at low and high risk.383
An observational study (SEER
database) in more than 35,000 patients with PTC limited to the thyroid
gland suggests that survival is similar whether (or not) patients are treated
in the first year after diagnosis and whether they undergo lobectomy or
total thyroidectomy.384
Another study of 2784 patients with differentiated
thyroid carcinoma (86% with PTC) found that total thyroidectomy was
associated with increased survival in patients at high risk.243
A study in
52,173 patients found that total thyroidectomy reduces recurrence rates
and improves survival in patients with PTC of 1 cm or larger when
compared with lobectomy.385
For patients at lower risk who undergo lobectomy plus isthmusectomy,
completion of thyroidectomy is recommended for any one of the following
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Thyroid Carcinoma
MS-23
risk factors: large tumor (4 cm), gross positive resection margins, gross
extrathyroidal extension, confirmed contralateral disease, vascular
invasion, poorly differentiated disease, or confirmed nodal metastases.
While a retrospective study using the National Cancer Database has
shown that a sizable percentage of patients with differentiated thyroid
cancer receive RAI therapy following lobectomy,386
the panel does not
support this practice due to a lack of data showing benefit. Therefore, RAI
is not recommended following lobectomy for differentiated thyroid cancer.
PTC with lymphatic invasion or macroscopic multifocal disease (1 cm)
may warrant a completion thyroidectomy (see Primary Treatment in the
NCCN Guidelines for Papillary [Thyroid] Carcinoma); disease monitoring
(category 2B) is another option for these patients. Measurement of Tg and
anti-Tg antibodies may be useful for obtaining a postoperative baseline,
but data to interpret these antibodies in the setting of an intact thyroid lobe
are lacking.387
Levothyroxine therapy can be considered for these patients
to maintain low or normal TSH levels (see Principles of TSH Suppression
in the NCCN Guidelines for Thyroid Carcinoma). Disease monitoring is
sufficient for tumors resected with lobectomy with all of the following:
negative resection margins, no contralateral lesion, no suspicious lymph
node(s), and small (≤4 cm) PTCs. Levothyroxine therapy to reduce serum
TSH to low or low-normal concentrations can be considered for these
patients (see Principles of TSH Suppression in the NCCN Guidelines for
Thyroid Carcinoma).
Radioactive Iodine Therapy
Postoperative RAI administration is recommended when a number of
clinical factors predict a significant risk of recurrence, distant metastases,
or disease-specific mortality. Clinicopathologic factors can be used to
guide decisions about whether to use initial postoperative RAI (see
Clinicopathologic Factors in the NCCN Guidelines for Papillary [Thyroid]
Carcinoma). Algorithms can assist in decision-making about use of RAI in
different settings: 1) RAI is not typically indicated for patients classified as
having a low risk of recurrence/disease-specific mortality; 2) RAI is not
recommended after lobectomy; 3) RAI may be considered for patients
without gross residual disease, but data are conflicting regarding the
benefit of RAI in this setting; and 4) RAI is often used for patients with
known or suspected distant metastatic disease at presentation. However,
some patients may have metastatic disease that may not be amenable to
RAI therapy, which is also known as iodine-refractory disease (see
Treatment of Metastatic Disease Not Amenable to RAI Therapy in the
NCCN Guidelines for Papillary [Thyroid] Carcinoma). Even in the absence
of thyroid bed uptake, postoperative RAI treatment may be considered.
RAI is also often used to reduce the risk of recurrent thyroid cancer in
patients deemed higher-risk based on surgical pathology, even if there is
no evidence of structural or biochemical disease present initially in the
postoperative period (see Recurrent Disease in this Discussion).
All patients should be examined, and cross-sectional imaging (CT or MRI
of neck with contrast) should be used to evaluate gross residual disease.
Palpable neck disease should be surgically resected before any RAI
treatment. A negative pregnancy test is required before the administration
of RAI in women of childbearing potential. The administered activity of RAI
therapy should be adjusted for pediatric patients.388
Dose should also be
modified if higher than expected uptake, such as in the event of residual
thyroid uptake or distant metastasis.
For patients with unresectable gross residual disease in the neck (RAI
uptake absent) that is refractory to RAI, EBRT or IMRT can be considered
if disease is threatening vital structures, is viscerally invasive, or is rapidly
progressing (see Postsurgical Evaluation in the NCCN Guidelines for
Papillary [Thyroid] Carcinoma).3,299,300,389-391
Enrollment in a neoadjuvant
clinical trial should be considered. Patients with bulky, locoregional,
viscerally invasive disease or rapid progression should be referred to a
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Thyroid Carcinoma
MS-24
high-volume multidisciplinary institution, including referral to a radiation
oncologist. Patients with unresectable gross residual disease who
received upfront EBRT or IMRT and with absent RAI should be monitored,
or systemic therapy treatment may be considered.
Surveillance and Maintenance
The recommendations for surveillance and maintenance are described in
the algorithm (see Disease Monitoring in the NCCN Guidelines for
Papillary [Thyroid] Carcinoma). About 85% of patients are considered to
be low risk after surgery for papillary thyroid cancer.246
In patients treated
with lobectomy, disease monitoring following surgery includes physical
examination, TSH assessment, and periodic neck ultrasound. If abnormal
contralateral nodule or lymph nodes are found, then biopsy should be
carried out.
In patients who have had total (or near total) thyroidectomy and thyroid
remnant ablation, the ATA Guidelines define the absence of persistent
tumor (also known as no evidence of disease [NED]) as: 1) absence of
clinical evidence of tumor; 2) absence of imaging evidence of tumor; and
3) undetectable Tg levels (during either TSH suppression or TSH
stimulation) and absence of anti-Tg antibodies.3
Patients treated with total
thyroidectomy should be followed with physical examination and
measurement of TSH, Tg, and Tg ab. RAI imaging (TSH-stimulated
[during either TSH suppression or TSH stimulation]) can be considered in
patients at high risk for persistent or recurrent disease, distant metastases,
or disease-specific mortality; patients with previous RAI-avid metastases;
or patients with abnormal Tg levels, stable or increasing Tg ab, or
abnormal ultrasound results. A tumor is considered iodine-responsive if
follow-up iodine-123 or low-dose iodine-131 whole body diagnostic
imaging done 6 to 12 months after iodine-131 treatment is negative or
shows decreasing uptake compared to pretreatment scans.3
Favorable
response to iodine-131 treatment is also assessed through change in
volume of known iodine-concentrated lesions by CT or MRI, as well as by
decreasing unstimulated or stimulated Tg levels.3
A subgroup of patients at low risk (eg, micropapillary carcinomas entirely
confined to the thyroid gland) may only require periodic neck ultrasound
follow-up (without stimulated Tg or follow-up whole body imaging) as long
as their basal Tg remains low (see Disease Monitoring in the NCCN
Guidelines for Papillary [Thyroid] Carcinoma). Otherwise, long-term
ultrasound follow-up is not required. Note that Tg should be measured
using the same laboratory and the same assay, because Tg levels vary
widely between laboratories.3
Patients with clinically significant residual
disease can typically be identified by the trend in Tg levels over time.3
Non-RAI imaging—such as ultrasound of the central and lateral neck
compartments, neck CT, chest CT, or FDG-PET/CT—may be considered
if RAI imaging is negative and stimulated Tg is greater than 2 to 5 ng/mL.
High-risk factors include incomplete tumor resection, macroscopic tumor
invasion, and distant metastases in patients at high risk for persistent or
recurrent disease, distant metastases, or disease-specific mortality (see
Consideration for Initial Postoperative RAI Therapy in the NCCN
Guidelines for Papillary [Thyroid] Carcinoma).3
Recurrent Disease
The NCCN Panel agrees that surgery is the preferred therapy for
locoregional recurrent disease if the tumor is resectable (see Recurrent
Disease in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).
Cervical ultrasound, including the central and lateral compartments, is the
principal imaging modality when locoregional recurrence is suspected.3
Cross-sectional imaging with CT or MRI may also be valuable for
evaluation and surgical planning, especially when reliable high-resolution
diagnostic ultrasound is unavailable and/or there is suspicion of invasion
into the aerodigestive tract. In most cases, lesions suspicious for
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Thyroid Carcinoma
MS-25
locoregional recurrence, which are amenable to needle biopsy, should be
interrogated with FNA biopsy before surgery. Tg washout assay may be a
useful adjunct to FNA biopsy in these cases, particularly if cytology is
negative. Preoperative iodine whole body scan can be used to guide
subsequent use of RAI or other follow-up approach.
Clinically significant nodal recurrence in a previously undissected nodal
basin should be treated with a formal compartmental resection.3
In the
central neck, this is usually achieved through a unilateral level VI
dissection and, occasionally, a level VII dissection. In the lateral
compartment, a formal modified radical neck dissection—including levels
II, III, IV, and Vb—should be performed. Extending the dissection field into
levels I or Va may be necessary when these levels are clinically involved.
Selective dissection of individual nodal metastases (cherry picking) is not
considered adequate surgery for nodal disease in a previously
undissected field, and is not recommended in the NCCN Guidelines for
Thyroid Carcinoma. Clinically significant nodal recurrence detected in a
previously dissected nodal basin may be treated with a more focused
dissection of the region containing the metastatic disease. For example, a
level II recurrence detected in a patient who underwent a modified radical
neck dissection as part of the primary treatment may only require selective
dissection of level II. Likewise, a central neck recurrence detected in a
patient who underwent a central neck dissection as part of the primary
treatment may only require a focused resection of the region of
recurrence.
For unresectable locoregional recurrence, RAI treatment and EBRT or
IMRT are recommended if the iodine-131 imaging is positive.392
Local
therapies, such as ethanol ablation or RFA, are also an option if
available.393
EBRT or IMRT alone is another option in the absence of
iodine-131 uptake for select patients not responsive to other
therapies.300,394
EBRT improves local control in patients with gross residual
non-RAI–avid disease following surgery.293
When recurrent disease is
suspected based on progressively rising Tg values (basal or stimulated)
and negative imaging studies (including PET scans), RAI therapy can be
considered using an empirically determined dose of greater than or equal
to 100 mCi of iodine-131 (see Recurrent Disease in the NCCN Guidelines
for Papillary [Thyroid] Carcinoma). The NCCN Panel had a major
disagreement (category 3) about recommending post-treatment iodine-131
imaging in this setting, because some do not feel that these patients
should have imaging. No study has shown a decrease in morbidity or
mortality in patients treated with iodine-131 on the basis of increased Tg
measurements alone. In a long-term follow-up study, no survival
advantage was associated with empiric high-dose RAI in patients with
negative imaging.395
Further, potential long-term side effects (ie,
xerostomia, nasolacrimal duct stenosis, bone marrow and gonadal
compromise, the risk of hematologic and other malignancies) may negate
any benefit.396,397
Active surveillance may be considered for patients with
low-volume disease that is stable and distant from critical structures.
Metastatic Disease
RAI therapy may be used to treat metastatic disease that is iodine-avid, or
local therapies such as ethanol ablation, cryoablation, or RFA may be
used for these patients, if available. For metastatic disease not amenable
to RAI therapy, several therapeutic approaches are recommended,
depending on the site and number of tumor foci (see Treatment of
Metastatic Disease Not Amenable to RAI Therapy in the NCCN Guidelines
for Papillary [Thyroid] Carcinoma).3,398
Patients should continue to receive
levothyroxine to suppress TSH levels. If not already done, then genomic
testing should be done to identify potentially actionable mutations (eg,
ALK, NTRK, and RET gene fusions; DNA mismatch repair deficiency
[dMMR]; microsatellite instability [MSI]; tumor mutational burden [TMB]).
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Thyroid Carcinoma
MS-26
For skeletal metastases, consider surgical palliation for symptomatic or
asymptomatic tumors in weight-bearing extremities; other therapeutic
options are EBRT, SBRT, or other local therapies.303,304,399-401
Intravenous
bisphosphonate (eg, pamidronate or zoledronic acid) or denosumab
therapy may be considered for bone metastases; data show that these
agents prevent skeletal-related events.402-404
Embolization (or other
interventional procedures) of metastases can also be considered either
prior to resection or as an alternative to resection.399,405
RAI is not likely to
be curative, but improved survival has been observed in these
patients.184,406
For solitary or limited CNS lesions, either neurosurgical resection or SRS
is preferred (see the NCCN Guidelines for Central Nervous System
Cancers).305,306
For multiple CNS lesions, EBRT can be considered,293
as
well as surgical resection for select cases such as for acute
decompression (see Treatment of Metastatic Disease Not Amenable to
RAI Therapy in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).
For multiple or extensive CNS lesions, radiotherapy (SRS or whole brain
RT) is recommended, with resection in select cases. If whole brain RT is
used, then 30 Gy in 10 daily fractions, or 45 Gy in 1.8 Gy daily fractions if
good performance status, are acceptable dosing schedules.407
For clinically progressive or symptomatic disease, systemic therapy should
be considered. Recommended systemic therapy options include: 1)
lenvatinib (preferred) or sorafenib;320,326
2) clinical trials; 3) other small-
molecule kinase inhibitors if a clinical trial is not available; or 4) resection
of distant metastases and/or EBRT or IMRT.408,409
Lenvatinib and
sorafenib are category 1 options in this setting based on phase 3
randomized trials.320,326
The NCCN Panel feels that lenvatinib is the
preferred agent in this setting based on a response rate of 65% for
lenvatinib when compared with 12% for sorafenib, although these agents
have not been directly compared.318,320,326
The decision to use lenvatinib or
sorafenib should be individualized for each patient based on likelihood of
response and comorbidities. The efficacy of lenvatinib or sorafenib for
patients with brain metastases has not been established; therefore,
consultation with neurosurgeons and radiation oncologists is
recommended. Kinase inhibitors have been used as second-line therapy
for thyroid cancer.321,410
Lenvatinib was compared with placebo in patients with metastatic
differentiated thyroid cancer that was refractory to RAI in a phase 3
randomized trial.320
Patients receiving lenvatinib had a progression-free
survival (PFS) of 18.3 months compared with 3.6 months for those
receiving placebo (HR, 0.21; 99% CI, 0.14–0.31; P .001). Six treatment-
related deaths occurred in the lenvatinib group. A prespecified subset
analysis of this trial found that the PFS benefit of lenvatinib compared to
placebo was maintained in both older (65 years) and younger (≤65 years)
patients. Furthermore, a longer median OS was observed in older patients
treated with lenvatinib compared to placebo (HR, 0.27; 95% CI, 0.31–0.91;
P = .20), although older patients also had higher rates of grade 3 and
greater adverse effects from treatment. These results suggest that
lenvatinib is an appropriate treatment option for patients of any age with
RAI-refractory differentiated thyroid cancer.411
Another phase 3 randomized trial compared sorafenib with placebo in
patients with RAI-refractory metastatic differentiated thyroid cancer.326
Patients receiving sorafenib had a PFS of 10.8 months compared with 5.8
months for those receiving placebo (HR, 0.59; 95% CI, 0.45–0.76; P
.0001). One treatment-related death occurred in the sorafenib group.
Hand-foot syndrome is common with sorafenib and may require dose
adjustments.
A phase 3 randomized trial compared cabozantinib to placebo in patients
with RAI-refractory differentiated thyroid cancer that progressed during or
after treatment with one or two vascular endothelial growth factor receptor
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Thyroid Carcinoma
MS-27
(VEGFR) TKIs (including lenvatinib and sorafenib).360
Analyses of the ITT
population (n = 187) showed that the median PFS was not reached in
patients receiving cabozantinib, compared with 1.9 months for those
receiving placebo (HR, 0.22; 99% CI, 0.13–0.36; P .0001). Serious
treatment-related adverse events occurred in 16% of patients in the
cabozantinib arm, compared with 2% in the placebo arm, though no
treatment-related deaths occurred. Cabozantinib is a category 1 option for
patients with disease progression after lenvatinib and/or sorafenib.
Other commercially available small-molecule kinase inhibitors may also be
considered for progressive and/or symptomatic disease if a clinical trial is
not available—including vemurafenib or dabrafenib (for BRAF-positive
disease), larotrectinib or entrectinib (for NTRK gene fusion-positive
disease), selpercatinib or pralsetinib (for RET fusion-positive disease),
axitinib, everolimus, pazopanib, sunitinib, vandetanib, or cabozantinib—
although some of these have not been approved by the FDA for
differentiated thyroid cancer (see Principles of Kinase Inhibitor Therapy in
Advanced Thyroid Carcinoma in the NCCN Guidelines for Thyroid
Carcinoma). Note that kinase inhibitor therapy may not be appropriate for
patients with stable or slowly progressive indolent disease,320,326,362,412,413
and caution should be used in patients with untreated CNS metastases
due to the associated bleeding risk.414
The anti-PD-1 antibody
pembrolizumab is also an option for patients with TMB-high (TMB-H) (≥10
mutations/megabase [mut/Mb]) disease.352
Active surveillance is often
appropriate for asymptomatic patients with indolent disease and no brain
metastasis.321,362
Palliative care is recommended as indicated for patients
with advanced and progressive disease (see the NCCN Guidelines for
Palliative Care, available at www.NCCN.org).
Follicular Thyroid Carcinoma
The diagnosis and treatment of papillary and follicular thyroid carcinoma
are similar; therefore, only the important differences in the management of
follicular carcinoma are highlighted. The diagnosis of follicular thyroid
carcinoma requires evidence of invasion through the capsule of the nodule
or the presence of vascular invasion.48,415
Unlike PTC, FNA is not specific
for follicular thyroid carcinoma and accounts for the main differences in
management of the two tumor types.56,62,97,416
The FNA cytologic diagnosis
of “[suspicious for] follicular neoplasm” will prove to be a benign follicular
adenoma in 80% of cases. However, 20% of patients with follicular
neoplasms on FNA are ultimately diagnosed with follicular thyroid
carcinoma when the final pathology is assessed. Molecular diagnostic
testing may be useful to determine the status of follicular lesions or lesions
of indeterminate significance (including follicular neoplasms, AUS, or
FLUS) as more or less likely to be malignant based on the genetic profile.
Because most patients with follicular neoplasms on FNA actually have
benign disease, total thyroidectomy is recommended only if radiographic
evidence or interoperative findings of extrathyroidal extension or tumor
larger than 4 cm in diameter are apparent at the time of surgery, or if the
patient opts for total thyroidectomy to avoid a second procedure (ie,
completion thyroidectomy) if cancer is found at pathologic review.415,417
Otherwise, lobectomy plus isthmusectomy is advised as the initial surgery.
If invasive follicular thyroid carcinoma (widely invasive or encapsulated
angioinvasive with four or more vessels) is found on the final histologic
sections after lobectomy plus isthmusectomy, prompt completion of
thyroidectomy is recommended (see Primary Treatment in the NCCN
Guidelines for Follicular [Thyroid] Carcinoma).
Completion thyroidectomy may also be recommended for tumors that, on
final histologic sections after lobectomy plus isthmusectomy, are identified
as minimally invasive follicular thyroid carcinomas or encapsulated
angioinvasive with less than four vessels. Minimally invasive cancer is
characterized as an encapsulated tumor with microscopic capsular
invasion and without vascular invasion.3
It is preferred for minimally
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Thyroid Carcinoma
MS-28
invasive cancers, as well as NIFTP tumors, to simply be followed carefully,
because minimally invasive follicular carcinomas and NIFTP usually have
an excellent prognosis. Although deaths attributed to minimally invasive
follicular carcinoma do occasionally occur, the panel feels that the benefit
of completion thyroidectomy for small minimally invasive follicular cancers
may not justify the additional morbidity.
The other features of management and follow-up for follicular thyroid
carcinoma are similar to those of PTC. Clinicopathologic factors can be
used to guide decisions about whether to administer initial postoperative
RAI (see Clinicopathologic Factors in the NCCN Guidelines for Follicular
[Thyroid] Carcinoma). The NCCN Guidelines provide algorithms to assist
in decision-making about use of RAI in different settings: 1) RAI is not
typically indicated for patients classified as having a low risk of
recurrence/disease-specific mortality; 2) RAI may be considered for
patients without gross residual disease, but data are conflicting regarding
the benefit of RAI in this setting; and 3) RAI is often used for patients with
known or suspected distant metastatic disease (see Clinicopathologic
Factors in the NCCN Guidelines for Follicular [Thyroid] Carcinoma).
RAI ablation may be used to destroy residual thyroid tissue when RAI
uptake is absent; alternatively, these patients may be followed without RAI
ablation. Iodine-131 ablation and post-treatment imaging (with
consideration of dosimetry for distant metastasis) are recommended for
suspected or proven iodine-131–avid metastatic foci (see RAI Being
Considered Based on Clinicopathologic Features in the NCCN Guidelines
for Follicular [Thyroid] Carcinoma). In patients with known or suspected
distantly metastatic disease, radioiodine diagnostic imaging (iodine-123 or
iodine-131) with adequate TSH stimulation (thyroid withdrawal or
thyrotropin alfa) before iodine-131 therapy is administered may be
considered, but the problem of stunning should be considered (see section
on Diagnostic Whole Body Imaging and Thyroid Stunning in this
Discussion). For patients who have a central neck recurrence,
preoperative vocal cord assessment should be considered (see Recurrent
Disease in the NCCN Guidelines for Follicular [Thyroid] Carcinoma).
Hürthle Cell Carcinoma
This tumor (also known as oxyphilic cell carcinoma) is usually assumed to
be a variant of follicular thyroid carcinoma,189,418
although the prognosis of
Hürthle cell carcinoma is worse.164,415,417,419,420
The Hürthle cell variant of
PTC is rare and seems to have a prognosis similar to follicular
carcinoma.421
Historically, studies showed that molecular diagnostics did
not perform well for Hürthle cell neoplasms.83,87,88
However, with the
advent of newer genomic tests, the validity for Hürthle cell carcinoma is
improving (see FNA Results in this Discussion, above).88,89
The management of Hürthle cell carcinoma is almost identical to follicular
thyroid carcinoma, except that 1) locoregional nodal metastases may be
more common, and therefore therapeutic lymph node dissections of the
affected compartment may be needed for clinically apparent biopsy-
proven disease; and 2) metastatic Hürthle cell tumors are less likely to
concentrate iodine-131 (see Papillary Thyroid Carcinoma: Surgical
Therapy in this Discussion).422
Postoperative EBRT or IMRT can be
considered for: 1) unresectable primary Hürthle cell lesions that do not
concentrate iodine-131 if disease is threatening vital structures; and 2)
unresectable locoregional recurrence (see Postsurgical Evaluation and
Recurrent Disease in the NCCN Guidelines for Hürthle Cell [Thyroid]
Carcinoma), similar to the management for follicular thyroid carcinoma.
Clinicopathologic factors can be used to guide decisions about whether to
use initial postoperative RAI (see Clinicopathologic Factors in the NCCN
Guidelines for Hürthle Cell [Thyroid] Carcinoma). The NCCN Guidelines
provide algorithms to assist in decision-making about use of RAI in
different settings: 1) RAI is not typically indicated for patients classified as
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having a low risk of recurrence/disease-specific mortality; 2) RAI may be
considered for patients without gross residual disease, but data are
conflicting regarding the benefit of RAI in this setting; and 3) RAI is often
used for patients with known or suspected distant metastatic disease (see
Clinicopathologic Factors in the NCCN Guidelines for Hürthle cell [Thyroid]
Carcinoma).
RAI therapy has been reported to decrease the risk of locoregional
recurrence and is recommended for unresectable disease with positive
iodine-131 imaging. Iodine-131 therapy (100–150 mCi) may be considered
after thyroidectomy for patients with rising or newly elevated Tg levels who
have negative scans (including FDG-PET) (see Recurrent Disease in the
NCCN Guidelines for Hürthle Cell [Thyroid] Carcinoma).164
Pretreatment
radioiodine diagnostic imaging (iodine-123 or iodine-131) with adequate
TSH stimulation (thyroid withdrawal or thyrotropin alfa) may be considered
in patients with known or suspected distantly metastatic disease (see RAI
Being Considered Based on Clinicopathologic Features in the NCCN
Guidelines for Hürthle Cell [Thyroid] Carcinoma). Since Hürthle cell
carcinoma tends to be non–iodine-avid, negative scans that were done
without single-photon emission CT (SPECT) are likely to have missed
distant structural disease. Therefore, if Tg is high and/or pathology is high-
risk, then FDG-PET is indicated.
Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) arises from the neuroendocrine
parafollicular C cells of the thyroid.423-426
Sporadic MTC accounts for about
80% of all cases of the disease. The remaining cases consist of inherited
tumor syndromes, such as: 1) MEN type 2A (MEN2A), which is the most
common type; and 2) MEN2B.427,428
Familial MTC is now viewed as a
variant of MEN2A.423,424,429
Sporadic disease typically presents in the fifth
or sixth decade of life. Inherited forms of the disease tend to present at
earlier ages.423,424
The 5-year relative survival for stages I to III is about
93%, whereas 5-year survival for stage IV is about 28%.168,189
Because the
C cells are predominantly located in the upper portion of each thyroid lobe,
patients with sporadic disease typically present with upper pole nodules.
Metastatic cervical adenopathy appears in about 50% of patients at initial
presentation. Symptoms of upper aerodigestive tract compression or
invasion are reported by up to 15% of patients with sporadic disease.430
Distant metastases in the lungs or bones cause symptoms in 5% to 10%
of patients. Many patients with advanced MTC can have diarrhea, Cushing
syndrome, or facial flushing, because the tumor can secrete calcitonin and
sometimes other hormonally active peptides (ie, adrenocorticotropic
hormone [ACTH], calcitonin gene-related peptide [CGRP]). Treatment with
somatostatin analogs (eg, octreotide, lanreotide) may be useful in patients
with these symptoms.431
Patients with unresectable or metastatic disease
may have either slowly progressive or rapidly progressive disease.
Nodule Evaluation and Diagnosis
Patients with MTC can be identified by using pathologic diagnosis or by
prospective genetic screening. Separate pathways are included in the
algorithm (see Clinical Presentation in the NCCN Guidelines for Medullary
[Thyroid] Carcinoma) depending on the method of identification.
Sporadic MTC
Sporadic MTC is usually suspected after FNA of a solitary nodule (see
Nodule Evaluation in the NCCN Guidelines for Thyroid Carcinoma).
Reports suggest that about 3% of patients with nodular thyroid disease will
have an increased serum calcitonin level when measured by a sensitive
immunometric assay; 40% of these patients will have MTC at
thyroidectomy.432-434
However, routine measurement of the basal serum
calcitonin concentration is not recommended by the NCCN Panel for
evaluating a patient with nodular thyroid disease because of: 1) the
expense of screening all thyroid nodules and only finding a few cases of
MTC; 2) the lack of confirmatory pentagastrin stimulation testing; and 3)
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the resulting need for thyroidectomy in some patients who have benign
thyroid disease.435,436
The ATA is equivocal about routine calcitonin
measurement.3
Inherited MTC
For patients with known kindreds with inherited MTC, prospective family
screening with testing for mutant RET genes can identify disease carriers
long before clinical symptoms or signs are noted.425,426
The traditional
approach of stimulating secretion of calcitonin by either pentagastrin or
calcium infusion to identify patients with MTC is no longer recommended,
because elevated calcitonin is not a specific or adequately sensitive
marker for MTC437
and because pentagastrin is no longer available in the
United States. When MEN2A is suspected, the NCCN Guidelines
recommend measurement of calcium levels with (or without) serum intact
parathyroid hormone levels (see Additional Workup in the NCCN
Guidelines for Medullary [Thyroid] Carcinoma). Compared with sporadic
disease, the typical age of presentation for familial disease is the third or
fourth decade of life, without gender preference. In patients with MEN2A,
signs or symptoms of hyperparathyroidism or pheochromocytoma rarely
present before those of MTC, even in the absence of screening.
All familial forms of MTC and MEN2 are inherited in an
autosomal-dominant fashion. Mutations in the RET proto-oncogene are
found in at least 95% of kindreds with MEN2A and 88% of cases of familial
MTC.425,426,438
The RET proto-oncogene codes for a cell
membrane-associated tyrosine kinase receptor for a glial, cell line-derived
neurotrophic factor. Mutations associated with MEN2A and familial MTC
have been primarily identified in several codons of the cysteine-rich
extracellular domains of exons 10, 11, and 13; MEN2B and some familial
MTC mutations are found within the intracellular exons 14 to 16.423,424
Somatic mutations in exons 11, 13, and 16 have also been found in at
least 25% of sporadic MTC tumors—particularly the codon 918 mutation
that activates the tyrosine kinase function of the receptor—and are
associated with poorer prognosis of the patient.
About 6% of patients with clinically sporadic MTC carry a germline RET
mutation, leading to identification of new kindreds with multiple (previously
undiagnosed) affected individuals.439,440
Germline testing for RET
proto-oncogene mutations with genetic counseling by a physician or
genetic counselor is recommended for all patients with newly diagnosed,
clinically apparent, sporadic MTC.441
If a germline RET mutation is found,
then mutation testing should also be done for family members. MTC can
involve difficult ethical decisions for clinicians if parents or guardians
refuse screening and/or treatment for children with possible MTC.442
Principles regarding genetic risk assessment can be found in the NCCN
Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian,
and Pancreatic (available at www.NCCN.org).
The generally accepted preoperative workup includes measurement of
serum markers (basal serum calcitonin and serum carcinoembryonic
antigen [CEA]) and screening of patients with germline RET
proto-oncogene mutations for pheochromocytoma (MEN2A and MEN2B)
and hyperparathyroidism (MEN2A). Before surgery for MTC, it is important
to diagnose and address coexisting pheochromocytoma to avoid
hypertensive crisis during surgery (see
Pheochromocytoma/Paraganglioma in the NCCN Guidelines for
Neuroendocrine Tumors, available at www.NCCN.org).
Pheochromocytoma can be removed using laparoscopic
adrenalectomy.423,424,443
Preoperative thyroid and neck ultrasound
(including central and lateral neck compartments) is recommended.
Contrast-enhanced CT of neck/chest and liver MRI or 3-phase CT of liver
can be considered as clinically indicated, such as in cases of high burden
of disease, calcitonin greater than 400 pg/mL, or elevated CEA levels.
Distant metastasis does not contraindicate surgery.423,424
Liver imaging is
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Patients with pheochromocytomas must be treated preoperatively with
alpha-adrenergic blockade (phenoxybenzamine) or with
alpha-methyltyrosine to avoid a hypertensive crisis during surgery. Forced
hydration and alpha-blockade are necessary to prevent hypotension after
the tumor is removed. After institution of alpha-blockade and hydration,
beta-adrenergic blockade may be necessary to treat tachyarrhythmia.
Total thyroidectomy and bilateral central neck dissection (level VI) are
indicated in all patients with MTC whose tumor is 1 cm or larger or who
have bilateral thyroid disease; total thyroidectomy is recommended and
neck dissection can be considered for those whose tumor is smaller than 1
cm and for unilateral thyroid disease (see Primary Treatment in the NCCN
Guidelines for Medullary [Thyroid] Carcinoma).374,430
Given the risks of
thyroidectomy in very young children, referral to a surgeon and team with
experience in pediatric thyroid surgery is advised.
If a patient with inherited disease is diagnosed early enough, the
recommendation is to perform a prophylactic total thyroidectomy by age 5
years or when the mutation is identified (in older patients), especially in
patients with codon 609, 611, 618, 620, 630, or 634 RET
mutations.423,424,458
Note that C634 mutations are the most common
mutations.423,424
Total thyroidectomy is recommended in the first year of
life or at diagnosis for patients with MEN2B who have codon 883 RET
mutations, 918 RET mutations, or compound heterozygous (V804M +
E805K, V804M + Y806C, or V804M + S904C) RET mutations (see Clinical
Presentation in the NCCN Guidelines for Medullary [Thyroid] Carcinoma),
because these RET mutations carry the highest risk for MTC (ie, level
D).423,424,459
However, for patients with codon 768, 790, 791, 804, and 891 RET (risk
level A) mutations, the lethality of MTC may be lower than with other RET
mutations.423,424,459,460
In patients with these less high-risk (ie, lower-risk
level A) RET mutations, annual basal calcitonin testing and annual
ultrasound are recommended; total thyroidectomy and central node
dissection may be deferred if these tests are normal, there is no family
history of aggressive MTC, and the family agrees to defer surgery (see
Additional Workup in the NCCN Guidelines for Medullary [Thyroid]
Carcinoma).423,424,461,462
Delaying thyroidectomy may also be appropriate
for children with lower-risk mutations (ie, level A) because of the late onset
of MTC development.423,424,460,461,463
A study found no evidence of
persistent or recurrent MTC 5 years or more after prophylactic total
thyroidectomy in young patients with RET mutations for MEN2A; longer
follow-up is necessary to determine if these patients are cured.464
Variations in surgical strategy for MTC depend on the risk for locoregional
node metastases and on whether simultaneous parathyroid resection for
hyperparathyroidism is necessary.423,424
A bilateral central neck dissection
(level VI) can be considered for all patients with MEN2B. For those
patients with MEN2A who undergo prophylactic thyroidectomy, therapeutic
ipsilateral or bilateral central neck dissection (level VI) is recommended if
patients have an increased calcitonin or CEA test or if ultrasound shows a
thyroid or nodal abnormality. Similarly, more extensive lymph node
dissection (levels II–V) is considered for these patients with primary
tumor(s) 1 cm or larger in diameter (0.5 cm for patients with MEN2B) or
for patients with central compartment lymph node metastases (see
Primary Treatment in the NCCN Guidelines for Medullary [Thyroid]
Carcinoma).
With a concurrent diagnosis of hyperparathyroidism in MEN2A or familial
MTC, the surgeon should leave or autotransplant the equivalent mass of
one normal parathyroid gland if multiglandular hyperplasia is present.
Cryopreservation of resected parathyroid tissue should be considered to
allow future implantation in the event of iatrogenic hypoparathyroidism.
Disfiguring radical node dissections do not improve prognosis and are not
indicated. In the presence of grossly invasive disease, more extended
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procedures with resection of involved neck structures may be appropriate.
Function-preserving approaches are preferred. In some patients, MTC is
diagnosed after thyroid surgery. In these patients, additional workup is
recommended to ascertain whether they have RET proto-oncogene
mutations (eg, exons 10, 11, 13–16), which will determine whether they
need additional surgery (eg, completion thyroidectomy and/or neck
dissection) (see Additional Workup in the NCCN Guidelines for Medullary
[Thyroid] Carcinoma).
Adjuvant RT
EBRT and IMRT have not been adequately studied as adjuvant therapy in
MTC.301,423,465
Slight improvements in local DFS have been reported after
EBRT for selected patients, such as those with extrathyroidal invasion or
extensive locoregional node involvement.466
However, most centers do not
have extensive experience with adjuvant EBRT or IMRT for this disease.
While therapeutic EBRT or IMRT may be considered for grossly
incomplete resection when additional attempts at surgical resection have
been ruled out, adjuvant EBRT or IMRT is rarely recommended (see
Primary Treatment in the NCCN Guidelines for Medullary [Thyroid]
Carcinoma).423,424
EBRT or IMRT can also be given to palliate painful or
progressing bone metastases.303,304,401,423,424
There is little evidence
regarding appropriate treatment volumes for use of RT for MTC, but
guidance regarding EBRT dose and fractionation is provided in the
Principles of Radiation and Radioactive Iodine Therapy: External Beam
Radiation Therapy in the NCCN Guidelines for Thyroid Carcinoma.
Persistently Increased Calcitonin
Basal serum concentrations of calcitonin and CEA should be measured 2
or 3 months postoperatively. About 80% of patients with palpable MTC
and 50% of those with nonpalpable but macroscopic MTC who undergo
supposedly curative resection have serum calcitonin values indicative of
residual disease. Those patients with residual disease may benefit from
further evaluation to detect either residual resectable disease in the neck
or the presence of distant metastases. Patients with detectable basal
calcitonin or elevated CEA who have negative imaging and who are
asymptomatic may be followed (see Surveillance in the NCCN Guidelines
for Medullary [Thyroid] Carcinoma). Patients with a basal serum calcitonin
value greater than 1000 pg/mL—and with no obvious MTC in the neck and
upper mediastinum—probably have distant metastases, most likely in the
liver. However, occasionally patients have relatively low serum CEA and
calcitonin levels but have extensive metastatic disease; initial
postoperative imaging is therefore reasonable despite the absence of very
high serum markers.
The prognosis for patients with postoperative hypercalcitoninemia
depends primarily on the extent of disease at the time of initial surgery. In
a study of 31 patients (10 patients with apparently sporadic disease, 15
patients with MEN2A, and 6 patients with MEN2B), the 5- and 10-year
survival rates were 90% and 86%, respectively.467
Two studies have
reported higher mortality rates for patients with high postoperative serum
calcitonin values, with more than 50% of patients having a recurrence
during a mean follow-up of 10 years.449,468
Routine lymphadenectomy or
excision of palpable tumor generally fails to normalize the serum calcitonin
concentrations in such patients; therefore, some have focused on
detection and eradication of microscopic tumor deposits with a curative
intent in patients without distant metastases. Extensive dissection to
remove all nodal and perinodal tissue from the neck and upper
mediastinum was first reported to normalize the serum calcitonin levels in
4 of 11 patients at least 2 years postoperatively.469
In subsequent larger
studies, 20% to 40% of patients undergoing microdissection of the central
and bilateral neck compartments were biochemically cured, with minimal
perioperative morbidity.470,471
When repeat surgery is planned for curative
intent, preoperative assessment should include locoregional imaging (ie,
ultrasonography of the neck and upper mediastinum) and attempts to
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exclude patients with distant metastases, which may include
contrast-enhanced CT or MRI of the neck, chest, and abdomen.471
Postoperative Management and Surveillance
Calcitonin is very useful for surveillance, because this hormone is only
produced in the parafollicular cells. Thus, measurements of serum
calcitonin and CEA levels are the cornerstone of postoperative
assessment for residual disease (see Management 2–3 Months
Postoperative in the NCCN Guidelines for Medullary [Thyroid] Carcinoma).
For patients with a detectable basal calcitonin or elevated CEA level, neck
ultrasound is recommended. Patients with undetectable calcitonin levels
and normal CEA levels can subsequently be followed with annual
measurements of serum markers. Additional studies or more frequent
testing can be done for those with significantly rising calcitonin or CEA.
Nonetheless, the likelihood of significant residual disease is very low in
patients with an undetectable basal calcitonin level in a sensitive assay. If
the patient has MEN2, annual screening for pheochromocytoma (MEN2B
or MEN2A) and hyperparathyroidism (MEN2A) should also be performed.
For some low-risk RET mutations (eg, codons 768, 790, 804, or 891), less
frequent screening may be appropriate.
Patients with detectable serum markers (ie, calcitonin levels ≥150 pg/mL)
should have CT or MRI of the neck, chest, and liver. Bone scan and MRI
of axial skeleton should be considered in select patients such as those
with very elevated calcitonin levels.423,424
The NCCN Panel recognizes that
many different imaging modalities may be used to examine for residual or
metastatic tumor, but there is insufficient evidence to recommend any
particular choice or combination of tests.423,424
For patients with asymptomatic disease and detectable markers in whom
imaging fails to identify foci of disease, the NCCN Panel recommends
conservative surveillance with repeat measurement of the serum markers
every 6 to 12 months. Additional imaging studies (eg, FDG PET/CT, Ga-
68 DOTATATE, or MRI with contrast of the neck, chest, and abdomen with
liver protocol) may be indicated depending on calcitonin/CEA doubling
time. For patients who are asymptomatic with abnormal markers and
repeated negative imaging, continued disease monitoring or consideration
of cervical reoperation is recommended if primary surgery was incomplete.
For the patient with increasing serum markers, more frequent imaging may
be considered. Outside of clinical trials, no therapeutic intervention is
recommended on the basis of abnormal markers alone.
Recurrent or Persistent Disease
Kinase inhibitors may be appropriate for select patients with recurrent or
persistent MTC that is not resectable (see Recurrent or Persistent Disease
in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Although
kinase inhibitors may be recommended for patients with MTC, it is
important to note that kinase inhibitors may not be appropriate for patients
with stable or slowly progressing indolent disease.321,472,473
Vandetanib and
cabozantinib are oral receptor kinase inhibitors that increase PFS in
patients with metastatic MTC.454,457,474-476
RET inhibitors that are FDA-
approved for RET-mutated MTC include selpercatinib and pralsetinib.350,351
Vandetanib is a multitargeted kinase inhibitor; it inhibits RET, VEGFR, and
endothelial growth factor receptor (EGFR).454
In a phase III randomized
trial in patients with unresectable, locally advanced, or metastatic MTC (n
= 331), vandetanib increased PFS when compared with placebo (HR,
0.46; 95% CI, 0.31–0.69; P .001); OS data are not yet available.454
A
post-hoc subgroup analysis including 184 patients with symptomatic and
progressive disease at baseline also showed increased PFS (HR, 0.43;
95% CI, 0.28–0.64; P .001) in patients who received vandetanib,
compared to the placebo, although time to worsening pain was not
significantly different between the two groups (HR, 0.67; 95% CI, 0.43–
1.04; P = .07).477
In this subgroup, the overall response rate (ORR) was
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37% in the patients who received vandetanib and 2% in patients who
received the placebo (P .001). The FDA approved the use of vandetanib
for patients with locally advanced or metastatic MTC who are not eligible
for surgery and whose disease is causing symptoms or growing.455
However, access is restricted through a vandetanib Risk Evaluation and
Mitigation Strategy (REMS) program because of potential cardiac
toxicity.478
The NCCN Panel recommends vandetanib (category 1) as a
preferred option for patients with recurrent or persistent MTC (see
Recurrent or Persistent Disease in the NCCN Guidelines for Medullary
[Thyroid] Carcinoma).
Cabozantinib is a multitargeted kinase inhibitor that inhibits RET,
VEGFR2, and MET. In a phase 3 randomized trial (EXAM) in patients with
locally advanced or metastatic MTC (n = 330), cabozantinib increased
median PFS when compared with placebo (11.2 vs. 4.0 months; HR, 0.28;
95% CI, 0.19–0.40; P .001).457
Following long-term follow-up, the
median OS for patients treated with cabozantinib was 26.6 months
compared to 21.1 months for placebo, although this difference was not
statistically significant (stratified HR, 0.85; 95% CI, .64–1.12, P = .24).479
Exploratory analyses have suggested that cabozantinib may have a
greater clinical benefit for medullary thyroid cancers harboring RET M918T
or RAS mutations, although prospective trials are needed to confirm.479,480
In 2012, the FDA approved the use of cabozantinib for patients with
progressive, metastatic MTC.456
The NCCN Panel recommends
cabozantinib (category 1) as a preferred option based on the phase III
randomized trial and FDA approval (see Recurrent or Persistent Disease
in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Rare adverse
events with cabozantinib include severe bleeding and gastrointestinal
perforations or fistulas; severe hemorrhage is a contraindication for
cabozantinib.
RET mutations account for a significant percentage of MTC cases,481,482
supporting investigation into the impact of recently developed RET
inhibitors on RET-mutated MTC. The phase I–II LIBRETTO-001 study
evaluated the efficacy of the RET inhibitor selpercatinib in 143 patients
with RET-mutant MTC.350
In patients previously treated with vandetanib or
cabozantinib (n = 55), the ORR and 1-year PFS rates were 69% (95% CI,
55%–81%) and 82% (95% CI, 69%–90%), respectively. In patients with no
previous vandetanib or cabozantinib treatment (n = 88), the ORR and 1-
year PFS rates were 73% (95% CI, 62%–82%) and 92% (95% CI, 82%–
97%), respectively. The most commonly reported toxicities (grade 3 and 4)
were hypertension (21%), increased alanine aminotransferase (11%),
increased aspartate aminotransferase (9%), hyponatremia (8%), and
diarrhea (6%). Dose reductions due to treatment-related adverse events
were reported in 30% of patients. Pralsetinib, another RET inhibitor, was
evaluated in the phase I–II ARROW study, which included 92 patients with
RET-mutant MTC.483
The ORR was 60% (95% CI, 46%–74%) in patients
previously treated with vandetanib or cabozantinib (n = 61) and 74% (95%
CI, 49%–91%) in patients with no previous vandetanib or cabozantinib
treatment (n = 22). Pralsetinib was generally well-tolerated, with the most
commonly reported grade 3–4 treatment-related adverse events being
hypertension (11%) and neutropenia (10%). These results are currently
reported in abstract form, and the ARROW study is ongoing and
continuing to enroll patients. In 2020, the FDA approved both of these
RET inhibitors for RET-mutated MTC requiring systemic therapy. Based
on the data and the FDA approvals, the NCCN Panel recommends
selpercatinib and pralsetinib as preferred options for patients with RET-
mutant disease (see Recurrent or Persistent Disease in the NCCN
Guidelines for Medullary [Thyroid] Carcinoma). RET somatic genotyping
may be done in patients who are germline wild-type or if germline status is
unknown.
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When locoregional disease is identified in the absence of distant
metastases, surgical resection is recommended with (or without)
postoperative EBRT or IMRT. For unresectable locoregional disease that
is symptomatic or progressing by Response Evaluation Criteria in Solid
Tumors (RECIST) criteria,484
the following options can be considered: 1)
RT (EBRT or IMRT); or 2) systemic therapy. Treatment can be considered
for symptomatic distant metastases (eg, those in bone); recommended
options include: 1) palliative resection, ablation (eg, radiofrequency,
embolization), or other regional treatment; 2) vandetanib (category 1); or
3) cabozantinib (category 1) (see Recurrent or Persistent Disease in the
NCCN Guidelines for Medullary [Thyroid] Carcinoma). These interventions
may be considered for asymptomatic distant metastases (especially for
progressive disease), but disease monitoring is acceptable given the lack
of data regarding alteration in outcome. If systemic therapy is indicated,
then vandetanib and cabozantinib are category 1 preferred options.
Selpercatinib or pralsetinib are preferred options for patients with RET-
mutation positive disease. Pembrolizumab is also an option for patients
with TMB-H (≥10 mut/Mb) disease, based on results of the phase II
KEYNOTE-158 trial, which included two patients with thyroid cancer.352
The NCCN Panel does not recommend treatment with systemic therapy
for increasing calcitonin or CEA alone.
In the setting of symptomatic disease or progression, the NCCN Panel
recommends systemic therapy or enrollment in a clinical trial. As stated
above for locoregional disease, preferred systemic therapy options include
vandetanib (category 1), cabozantinib (category 1), and selpercatinib or
pralsetinib for patients with RET-mutation positive disease. Other small-
molecule kinase inhibitors (ie, sorafenib, sunitinib, lenvatinib, pazopanib)
may be considered if clinical trials or the NCCN-preferred systemic
therapy options are not available or are not appropriate.334,485-490
If the
patient progresses on a preferred option, then systemic chemotherapy can
be administered using dacarbazine or combinations including
dacarbazine.423,491-493
Pembrolizumab is also an option for patients with
TMB-H (≥10 mut/Mb) disease (useful in certain circumstances).352
EBRT
or IMRT can be used for local symptoms. Intravenous bisphosphonate
therapy or denosumab can be considered for bone metastases.402-404
Best
supportive care is also recommended.
Results from clinical trials have shown the effectiveness of novel
multitargeted therapies including sunitinib,334,335
sorafenib,412,486
lenvatinib,489
and pazopanib488
in MTC. Severe or fatal side effects from
kinase inhibitors include bleeding, hypertension, and liver toxicity;
however, many side effects can be managed.362,365,408,413
Because some
patients may have indolent and asymptomatic disease, potentially toxic
therapy may not be appropriate.362
Novel therapies and the management of aggressive MTC have been
reviewed.315,423,494-497
Of interest, calcitonin levels decreased dramatically
after vandetanib therapy, which did not directly correlate with changes in
tumor volume; thus, calcitonin may not be a reliable marker of tumor
response in patients receiving RET inhibitor therapy.498
A phase 2 trial in
patients with progressive metastatic MTC assessed treatment using
pretargeted anti–CEA radioimmunotherapy with iodine-131.499
OS was
improved in the subset of patients with increased calcitonin doubling
times.500
Anaplastic Thyroid Carcinoma
ATCs are aggressive undifferentiated tumors, with a disease-specific
mortality approaching 100%.501
Patients with anaplastic carcinoma are
older than those with differentiated carcinomas, with a mean age at
diagnosis of approximately 71 years.502
Fewer than 10% of patients are
younger than 50 years, and 60% to 70% of patients are women.108,502
The
incidence of ATC is decreasing because of better management of
differentiated thyroid cancer and because of increased iodine in the
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Systemic Therapy
Systemic therapy recommendations are described in the algorithm (see
Systemic Therapy for Anaplastic Thyroid Carcinoma in the NCCN
Guidelines for Anaplastic [Thyroid] Carcinoma). When systemic therapy is
indicated, targeted therapy options are preferred. Dabrafenib plus
trametinib combination is an option for BRAF V600E mutation-positive
tumors,530
larotrectinib or entrectinib are options for NTRK gene fusion-
positive tumors,348,349,531
selpercatinib or pralsetinib are options for RET
fusion-positive disease,350,351
and pembrolizumab is an option for TMB-H
(≥10 mut/Mb) disease.352
Other recommended regimens include paclitaxel
and doxorubicin monotherapies.510
Doxorubicin combined with cisplatin is
an option based on a small randomized trial.532
Paclitaxel combined with
carboplatin and docetaxel combined with doxorubicin are also systemic
therapy options for patients with metastatic ATC, but these are category
2B options based on low-quality evidence510
and less panel consensus.
The NCCN Panel recommends molecular testing to help inform decisions
regarding systemic therapy and to determine eligibility for clinical trials.
The dosage and frequency of administration of all the recommended
systemic therapy agents are provided in the algorithm. Either concurrent
chemoradiation or chemotherapy alone regimens may be used depending
on the clinical setting; however, chemoradiation is generally more toxic. If
using chemoradiation, the ATA Guidelines recommend using weekly
chemotherapy regimens.510
A phase 2, open-label trial of 16 patients with BRAF V600E-mutated ATC
evaluated the efficacy and safety of dabrafenib 150 mg, twice daily, in
combination with trametinib 2 mg, once daily.530
The confirmed ORR was
69% (95% CI, 41%–89%), with seven responses ongoing. While duration
of response, PFS, and OS were not yet reached, the 12-month estimates
were 90%, 79%, and 80%, respectively. The combination was found to be
well-tolerated as evaluated in 100 patients across seven rare tumor types;
common adverse events included fatigue (38%), pyrexia (37%), and
nausea (35%).530
Based on these data, the FDA approved
dabrafenib/trametinib for ATC with BRAF V600E mutation in 2018.
A pooled analysis of three studies (a phase 1 including adults, a phase 1/2
involving children, and a phase 2 involving adolescents and adults)
studied the safety and efficacy of larotrectinib in patients with NTRK gene
fusion-positive tumors, including seven patients with thyroid cancer of
which one patient had ATC.348,533
For the whole population, the ORR was
75% (95% CI, 61%–85%) by independent review and 80% (95% CI, 67%–
90%) by investigator assessment.348,533
One hundred percent of the thyroid
cancers in this study responded to larotrectinib, with one complete
response and four partial responses.533
Larotrectinib was found to be well-
tolerated, as the majority (93%) of adverse events were grades 1 or 2 and
no treatment-related adverse events of grades 3 or 4 occurred in more
than 5% of patients.348
A pooled analysis from a phase II trial and two
phase I trials including 54 patients with NTRK gene fusion-positive cancer
(9% having thyroid cancer) showed an objective response rate of 57.4%
for entrectinib, another TRK inhibitor.349
Based on these data, the FDA
approved larotrectinib and entrectinib for treatment of patients with NTRK
gene fusion-positive tumors, and the panel also recommends NTRK
therapy options such as larotrectinib or entrectinib for patients with NTRK
gene fusion-positive metastatic ATC.
The phase I–II LIBRETTO-001 study evaluated the efficacy of the RET
inhibitor selpercatinib in 19 patients with previously treated RET fusion-
positive thyroid cancer (2 patients with anaplastic disease).350
The ORR
was 79% (95% CI, 54%–94%), and 1-year PFS was 64% (95% CI, 37%–
82%). In the ongoing phase I–II ARROW study, pralsetinib, another RET
inhibitor, is being evaluated in patients with RET fusion-positive disease
(NCT03037385). In an analysis including 9 patients with RET fusion-
positive thyroid cancer, the ORR was 89% (95% CI, 52%–100%) with
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durable responses (100% DCR).351
In 2020, the FDA approved both of
these RET inhibitors for RAI-refractory RET fusion-positive thyroid cancer
requiring systemic therapy.
The FDA approved the anti-PD-1 antibody pembrolizumab for treatment of
previously treated TMB-H (≥10 mut/Mb) solid tumors in 2020 based on
results of the phase II KEYNOTE-158 trial, which included two patients
with thyroid cancer.352
For the whole sample, the ORR was 29% (95% CI,
21%–39%). Grade 3–5 treatment-related adverse events were reported in
15% of the patients. A phase II study evaluated another anti-PD-1
antibody, spartalizumab, in 42 patients with locally advanced or metastatic
ATC.534
The ORR was only 19% (95% CI, 8.6%–34.1%), but was higher
for patients with PD-L1–positive disease (29%; 95% CI, 13.2%–48.7%)
and highest in patients with PD-L1 greater than 50% (35%; 95% CI,
14.2%–61.7%).
Treatment with anthracyclines and taxanes is generally not very effective
for advanced anaplastic disease, although some patients may show
disease response or have stable disease.510,527
Single-agent doxorubicin is
approved by the FDA for ATC. A randomized trial including 84 patients
with advanced thyroid cancer (not limited to ATC) showed an 11.6%
complete response rate in patients who received doxorubicin combined
with cisplatin, compared to a complete response in 0 patients who
received single-agent doxorubicin.532
ORR did not differ significantly
between the study arms (26% vs. 17%, respectively). Single-agent
paclitaxel may benefit some patients with newly diagnosed ATC;
increased survival has been reported in patients with stage IVB
disease.535-537
If weekly paclitaxel is used, the ATA Guidelines510
recommend using paclitaxel at 60 to 90 mg/m2
IV weekly and not the dose
previously reported in the study by Ain et al.537
Given the poor outcome with current standard therapy, all patients—
regardless of surgical resection—should be considered for clinical trials.
Previous clinical trials for ATC have tested therapies including
fosbretabulin (and its parent drug, combretastatin A4 phosphate [CA4P],
and crolibulin [EPC2407], which are vascular disrupting agents),
efatutazone (an oral PPAR gamma agonist), and novel multitargeted
therapies including bevacizumab with doxorubicin, sorafenib, sunitinib,
imatinib, and pazopanib.335,538-546
A trial in 80 patients (FACT) reported that
the addition of fosbretabulin—to a carboplatin/paclitaxel regimen—resulted
in a nonsignificant increase in median survival (5.2 vs. 4.0 months).538,547
Preliminary data suggest that ALK inhibitors may be effective in a subset
of patients with papillary thyroid cancer who have ALK gene fusions;
however, these ALK gene fusions are rarely reported in patients with
ATC.353-356
Hyperfractionated EBRT, combined with radiosensitizing doses of
doxorubicin, may increase the local response rate to about 80%, with a
subsequent median survival of 1 year.548
Distant metastases then become
the leading cause of death.549
Similar improvement in local disease control
has been reported with a combination of hyperfractionated RT and
doxorubicin-based regimens, followed by debulking surgery in responsive
patients or other multimodality approaches.527,550-552
IMRT may be useful to
reduce toxicity.465,510,553-557
However, the addition of larger doses of other
chemotherapeutic drugs has not been associated with improved control of
distant disease or with improved survival. Other radiosensitizing agents
that may be considered include docetaxel and paclitaxel with or without
carboplatin.535,537,554,558
Although optimal results have been reported with
hyperfractionated EBRT combined with chemotherapy, the NCCN Panel
acknowledges that considerable toxicity is associated with such treatment
and that prolonged remission is uncommonly reported.559
Multimodality therapy is recommended in patients with locally resectable
disease (see Treatment in the NCCN Guidelines for Anaplastic [Thyroid]
Carcinoma).510,538,553,560-564
Small retrospective studies have reported that
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- 1. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) Thyroid Carcinoma Version 3.2022 — November 1, 2022 Continue NCCN.org NCCN Guidelines for Patients® available at www.nccn.org/patients
- 2. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Panel Disclosures ð Endocrinology Þ Internal medicine † Medical oncology Ф Nuclear medicine ζ Otolaryngology ≠ Pathology ¥ Patient advocacy § Radiation/Radiation oncology ¶ Surgery/Surgical oncology * Writing Committee Member Continue *Robert I. Haddad, MD/Chair † Dana‑Farber/Brigham and Women’s Cancer Center *Lindsay Bischoff, MD/Vice‑Chair ð Vanderbilt‑Ingram Cancer Center Douglas Ball, MD ð The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Victor Bernet, MD ð Mayo Clinic Cancer Center Erik Blomain, MD, PhD § ¥ Stanford Cancer Institute Naifa Lamki Busaidy, MD ð The University of Texas MD Anderson Cancer Center Michael Campbell, MD ð UC Davis Comprehensive Cancer Center Paxton Dickson, MD ¶ St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center Quan‑Yang Duh, MD ¶ UCSF Helen Diller Family Comprehensive Cancer Center Hormoz Ehya, MD ≠ Fox Chase Cancer Center Whitney S. Goldner, MD ð Fred & Pamela Buffett Cancer Center Theresa Guo, MD ζ UC San Diego Moores Cancer Center Megan Haymart, MD Þ ð University of Michigan Rogel Cancer Center Shelby Holt, MD ¶ UT Southwestern Simmons Comprehensive Cancer Center Jason P. Hunt, MD ¶ Huntsman Cancer Institute at the University of Utah Andrei Iagaru, MD Ф Stanford Cancer Institute Fouad Kandeel, MD, PhD ð City of Hope National Medical Center Dominick M. Lamonica, MD Þ Ф Roswell Park Comprehensive Cancer Center Susan Mandel, MD, MPH ð Abramson Cancer Center at the University of Pennsylvania Stephanie Markovina, MD, PhD § Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine Bryan McIver, MD, PhD ð Moffitt Cancer Center Christopher D. Raeburn, MD ¶ University of Colorado Cancer Center Rod Rezaee, MD ¶ ζ Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute John A. Ridge, MD, PhD ¶ Fox Chase Cancer Center Mara Y. Roth, MD ð Fred Hutchinson Cancer Center Randall P. Scheri, MD ¶ Duke Cancer Institute Jatin P. Shah, MD, PhD ¶ Memorial Sloan Kettering Cancer Center Jennifer A. Sipos, MD ð The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Rebecca Sippel, MD ¶ University of Wisconsin Carbone Cancer Center Cord Sturgeon, MD ¶ Robert H. Lurie Comprehensive Cancer Center of Northwestern University Thomas N. Wang, MD, PhD ¶ O'Neal Comprehensive Cancer Center at UAB Lori J. Wirth, MD † Massachusetts General Hospital Cancer Center Richard J. Wong, MD ¶ Memorial Sloan Kettering Cancer Center Michael Yeh, MD ¶ UCLA Jonsson Comprehensive Cancer Center NCCN Susan Darlow, PhD Carly J. Cassara, MSc Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 3. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion NCCN Thyroid Carcinoma Panel Members Summary of the Guidelines Updates Thyroid Nodule Evaluation Nodule Evaluation (THYR‑1) Papillary Carcinoma FNA Results, Diagnostic Procedures, Preoperative or Intraoperative Decision‑Making Criteria, Primary Treatment (PAP‑1) Follicular Carcinoma FNA Results, Diagnostic Procedures, Primary Treatment (FOLL‑1) Hürthle Cell Carcinoma FNA Results, Diagnostic Procedures, Primary Treatment (HÜRT‑1) Medullary Carcinoma Clinical Presentation, Diagnostic Procedures, Primary Treatment (MEDU‑1) Germline Mutation of RET Proto‑oncogene (MEDU‑3) Anaplastic Carcinoma FNA or Core Biopsy Finding, Diagnostic Procedures, Establish Goals of Therapy, Stage (ANAP‑1) Systemic Therapy for Anaplastic Thyroid Carcinoma (ANAP‑A) Principles of TSH Suppression (THYR‑A) Principles of Kinase Inhibitor Therapy in Advanced Thyroid Carcinoma (THYR‑B) Principles of Radiation and Radioactive Iodine Therapy (THYR-C) Principles of Active Surveillance for Low-Risk Papillary Thyroid Cancer (THYR-D) Principles of Cancer Risk Assessment and Counseling (THYR-E) Staging The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN® ) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network® . All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2022. Clinical Trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at NCCN Member Institutions, click here: nccn.org/clinical_trials/member_ institutions.aspx. NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated. See NCCN Categories of Evidence and Consensus. NCCN Categories of Preference: All recommendations are considered appropriate. See NCCN Categories of Preference. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 4. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion Updates in Version 3.2022 of the NCCN Guidelines for Thyroid Carcinoma from Version 2.2022 include: PAP-9 • Treatment, systemic therapies modified (also PAP-10, PAP-11) Useful in certain circumstances, bullet added: Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options FOLL-8 • Treatment, systemic therapies modified (also FOLL-9, FOLL-10) Useful in certain circumstances, bullet added: Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options HÜRT-8 • Treatment, systemic therapies modified (also HÜRT-9, HÜRT-10) Useful in certain circumstances, bullet added: Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options Updates in Version 2.2022 of the NCCN Guidelines for Thyroid Carcinoma from Version 1.2022 include: MS-1 • The discussion has been updated to reflect the changes in the algorithm. THYR-1 • Footnote modified: The diagnosis of follicular carcinoma or Hürthle cell carcinoma requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Molecular diagnostics may be useful to allow reclassification of follicular lesions (ie, follicular neoplasm, AUS, FLUS) as either more or less likely to be benign or malignant based on the genetic profile. If molecular testing suggests papillary thyroid carcinoma, especially in the case of BRAF V600E, see PAP‑1. Molecular diagnostics specifically for medullary thyroid cancer across Bethesda III-VI nodules may identify these specific carcinomas given the challenges of cytology to explicitly identify them (category 2B). If molecular testing, in conjunction with clinical and ultrasound features, predicts a risk of malignancy comparable to the risk of malignancy seen with a benign FNA cytology (approximately 5% or less), consider nodule surveillance. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient. If molecular diagnostics are technically inadequate or not done, then repeat FNA. HÜRT-1 • Footnote modified: The diagnosis of Hürthle cell carcinoma requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Consider molecular diagnostics. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient. MEDU-1 • Clinical presentation: Medullary thyroid carcinoma on FNA by cytology or molecular diagnostics Updates in Version 1.2022 of the NCCN Guidelines for Thyroid Carcinoma from Version 3.2021 include: MS-1 • The discussion has been updated to reflect the changes in the algorithm. THYR-1 • Footnote modified: Estimated risk of malignancy is 6%–18% exclusive of NIFTP without NIFTP and 10%–30% with noninvasive follicular thyroid neoplasm with papillary‑like nuclear features (NIFTP). THYR-2 • Molecular Diagnostic Results Repeat FNA cytology and/or Consider molecular diagnostics • Treatment Molecular diagnostics not informative or with insufficient or degraded sample ◊ Nodule surveillance or Consider lobectomy or total thyroidectomy in select situations for definitive diagnosis/treatment or Consider repeat biopsy Molecular diagnostics suggestive of malignancy: Consider lobectomy or total thyroidectomy (depending on molecular results) for definitive diagnosis/treatment or Nodule surveillance Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 5. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion UPDATES Continued Updates in Version 1.2022 of the NCCN Guidelines for Thyroid Carcinoma from Version 3.2021 include: PAP-1 • Diagnostic Procedures Upper branch modified: ≥ 1 cm Lower branch modified: ≤1 cm • Preoperative or intraoperative decision-making criteria lower branch modified: Indications for total thyroidectomy or lobectomy (preferred), if all criteria present: • Primary Treatment Indications for total thyroidectomy or lobectomy: Lobectomy (preferred) No concerning lymph nodes: Lobectomy if high risk • Footnote added: See Principles of Active Surveillance PAP-2 • Clinical Presentation All of the following, bullet 3 modified: Tumor 1≤4 cm in diameter • Primary Treatment Lower branch, option removed: Consider thyroglobulin measurement and anti‑Tg antibodies 6–12 weeks post-op PAP-3 • Postsurgical Evaluation (also FOLL-2 and HURT-2) Unresectable lower pathway modified: For viscerally invasive disease or rapid progression, upfront EBRT/IMRT, neoadjuvant therapy may be most appropriate • Footnotes (also FOLL-2 and HURT-2) Footnote added: Even in the absence of thyroid bed uptake, RAI treatment may be considered. If higher than expected uptake (residual thyroid uptake or distant metastasis) change dose accordingly. Footnote added: A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. PAP-4 • Clinicopathological Factors RAI selectively recommended (if any present), bullet added: Vascular invasion • Consideration for Initial Postoperative use of RAI after Total Thyroidectomy (also FOLL-3 and HURT-3) RAI selectively recommended pathway modified: RAI ablation is recommended when the combination of individual clinical factors (such as the size extent of the primary tumor, histology, degree of lymphatic invasion, lymph node metastases, postoperative thyroglobulin, and age at diagnosis) predicts a significant risk of recurrence, distant metastases, or disease‑specific mortality • Footnotes Footnote added: Minimal extrathyroidal extension alone likely does not warrant RAI. (also FOLL-3 and HURT-3) Footnote modified: ie eg, poorly differentiated, tall cell, columnar cell, hobnail variants, diffuse sclerosing, and insular. PAP-6 • Known or Suspected Distant Metastatic Disease (also FOLL-5 and HURT-5) 6–12 weeks post-thyroidectomy pathway modified: Known or suspected distant metastases at presentation or elevated Tg 6–12 weeks post-thyroidectomy, no uptake pathway modified: Consider RAI adjuvant therapy and post‑treatment imaging (whole body RAI scan, consider PET scan) PAP-7 • Disease Monitoring: This page has been extensively revised. (Also FOLL-6 and HURT-6) PAP-8 • Recurrent Disease (also for FOLL-7 and HURT-7) Bullet 1 modified: Stimulated Rising or newly elevated Tg ≥ 1–10 ng/mL and negative imaging Locoregional recurrence pathway modified: Surgery (preferred) if resectable and/or Consider radioiodine treatment, if postoperative radioiodine imaging positive Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 6. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion UPDATES Continued Updates in Version 1.2022 of the NCCN Guidelines for Thyroid Carcinoma from Version 3.2021 include: PAP-9 • Treatment, systemic therapies modified (also PAP-10, PAP-11) Sub-bullet 1 added: Preferred Regimens Sub-sub-bullet 1 modified: consider Lenvatinib (category 1) Sub-bullet 2 added: Other Recommended Regimens Sub-sub-bullet 2 added: Sorafenib (category 1) Sub-bullet 3 added: Useful in Certain Circumstances Sub-sub-bullet 3 added: Cabozantinib (category 1) if progression after lenvatinib and/or sorafenib • Footnotes deleted (also PAP-10, PAP-11, FOLL-8, FOLL-9, FOLL-10, HURT-8, HURT-9, HURT-10) In a subset of patients (65 years of age), lenvatinib showed an overall survival benefit compared to placebo. Brose MS, et al. J Clin Oncol 2017;35:2692‑2699. The decision of whether to use lenvatinib (preferred) or sorafenib should be individualized for each patient based on likelihood of response and comorbidities. RAI therapy is an option in some patients with bone metastases and RAI sensitive disease. FOLL-1 • Primary Treatment Total thyroidectomy if invasive cancer, metastatic cancer, if radiographic evidence or intraoperative findings of extrathyroidal extension or tumor 4 cm in diameter, or patient preference perform therapeutic neck dissection of involved compartments for clinically apparent/biopsy-proven disease. (also HURT-1) FOLL-3 • Clinicopathological Factors (also HURT-3) RAI selectively recommended (if any present), bullet 2 modified: Minor vascular invasion (4 foci) RAI recommended (if any present), bullet 3 modified: Extensive vascular invasion (≥4 foci) FOLL-8 • Treatment, systemic therapies modified (also FOLL-9, FOLL-10, HURT-8, HURT-9, HURT-10) Sub-bullet 1 added: Preferred Regimens Sub-sub-bullet 1 modified: consider Lenvatinib (category 1) Sub-bullet 2 added: Other Recommended Regimens Sub-sub-bullet 2 added: Sorafenib (category 1) Sub-bullet 3 added: Useful in Certain Circumstances Sub-sub-bullet 3 added: Cabozantinib if progression after lenvatinib and/or sorafenib HÜRT-3 • Footnotes Footnote removed: Minimally invasive HCC is characterized as an encapsulated tumor with microscopic capsular invasion and without vascular invasion. MEDU-1 • Footnote modified: Germline mutation should prompt specific mutation testing in subsequent family members and genetic counseling. See Principles of Cancer Risk Assessment and Counseling • Footnote modified: Prior to germline testing, all patients should be offered genetic counseling either by their physician or a genetic counselor. See Principles of Cancer Risk Assessment and Counseling MEDU-5 • Disease Monitoring Detectable basal calcitonin or Elevated CEA, bullet 2 modified: If calcitonin ≥150 pg/mL, CT or MRI with contrast of neck, liver, and chest • Footnote added: It is unlikely that there will be radiographic evidence of disease when calcitonin is less than 150 pg/mL. ANAP-1 • Diagnostic procedures, bullet 7 modified: FDG PET/CT or MRI (skull base to mid‑thigh) • Establish goals of therapy, bullet 4 modified: Discuss palliative care options including airway management Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 7. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion UPDATES Continued Updates in Version 1.2022 of the NCCN Guidelines for Thyroid Carcinoma from Version 3.2021 include: ANAP-A 1 of 3 • Adjuvant/Radiosensitizing Chemotherapy Regimens Other recommended regimens modified: ◊ Docetaxel/doxorubicin: Docetaxel 60 mg/m2 IV, doxorubicin 60 mg/m2 IV (with pegfilgrastim) every 3-4 weeks or Docetaxel 20 mg/m2 IV, doxorubicin 20 mg/m 2 IV, weekly Other recommended regimens ◊ Added: Docetaxel 20mg/m2 IV Weekly ◊ Removed: cisplatin ◊ Removed: doxorubicin ANAP-A 2 of 3 • Systemic Therapy Regimens for Metastatic Disease Other recommended regimens modified: ◊ Paclitaxel/carboplatin (category 2B) ◊ Docetaxel/doxorubicin (category 2B) Useful in certain circumstances regimens added: ◊ Doxorubicin/cisplatin: Doxorubicin 60 mg/m 2 IV, cisplatin 40 mg/m 2 IV, Every 3 weeks ANAP-A 3 of 3 • Reference added: Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2021;31:337-386. THYR-A • Sub-bullet 1 modified: In general, patients with known structural residual carcinoma or at high risk for recurrence should have TSH levels maintained below 0.1 mU/L, whereas • Bullet 2 modified: Patients who remain disease free for several years can probably should have their TSH levels maintained within the reference range (0.5–2 mU/L). THYR-C 2 of 5 • Administered Activity Remnant ablation, sub-sub bullet 1 modified: If RAI ablation is used in T1b/T2 (1–4 cm), clinical N0 disease, inthe absence of other adverse pathologic, laboratory, or imaging features, 30-50 mCi of iodine-131 is recommended (category 1) following either thyrotropin alfa stimulation or thyroid hormone withdrawal. This dose of 30–50 mCi may also be considered (category 2B) for patients with T1b/T2 (1–4 cm) with small-volume N1a disease (fewer than 5 lymph node metastases 2 mm in diameter) and for patients with primary tumors 4 cm, clinical M0 with minor extrathyroidal extension. Adjuvant therapy, sub-bullet 1 modified: 50–150 100 mCi THYR-D • Principles of Active Surveillance for Low-Risk Papillary Thyroid Cancer: new to Guidelines THYR-E • Principles of Cancer Risk Assessment and Counseling: new to Guidelines Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 8. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion THYR‑1 Follicular or Hürthle cell neoplasma,b (Bethesda IV) Atypia of undetermined significance/ Follicular lesion of undetermined significanceb,c (AUS/FLUS) (Bethesda III) High clinical and/or radiographic suspicion of malignancyd No Primary Treatment (ANAP‑1) Primary Treatment (MEDU‑1) Primary Treatment (PAP‑1) FNA RESULTS TREATMENTe Diagnostic categories for FNA results reflect NCI state of the science conference, the Bethesda Classification. Cibas ES, Ali SZ. Thyroid 2017;27:1341‑1346. https://www.ncbi. nlm.nih.gov/pubmed/29091573. Cytology reports should be interpreted in light of terminology used by local cytopathologists. No Yes • Consider repeat FNAh • Consider diagnostic lobectomy (if Bethesda III on 2 or more occasions) • Consider molecular diagnosticsb (See THYR‑2) • Consider nodule surveillance as recommended by the ATA or TI-RADSg Consider lobectomy or total thyroidectomyf for definitive diagnosis/treatment Carcinoma or suspicious for carcinoma (Bethesda V or Vl) b Papillary or suspicious for papillary Medullary or suspicious for medullary Anaplastic or suspicious for anaplastic Yes Consider lobectomy or total thyroidectomyf for definitive diagnosis/treatment • Consider diagnostic lobectomy • Consider molecular diagnosticsb (See THYR‑2) • Consider nodule surveillance if low risk or patient preference as recommended by the ATA or TI-RADSg See PAP‑1 See FOLL‑1 See HÜRT‑1 High clinical and/or radiographic suspicion of malignancyd a Alternative term: Suspicious for follicular or Hürthle cell neoplasm. Estimated risk of malignancy is 15%–40%. Numbers may vary by institution or cytopathologist. b The diagnosis of follicular carcinoma or Hürthle cell carcinoma requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Molecular diagnostics may be useful to allow reclassification of follicular lesions (ie, follicular neoplasm, AUS, FLUS) as either more or less likely to be benign or malignant based on the genetic profile. If molecular testing suggests papillary thyroid carcinoma, especially in the case of BRAF V600E, see PAP‑1. Molecular diagnostics specifically for medullary thyroid cancer across Bethesda III-VI nodules may identify these specific carcinomas given the challenges of cytology to explicitly identify them (category 2B). If molecular testing, in conjunction with clinical and ultrasound features, predicts a risk of malignancy comparable to the risk of malignancy seen with a benign FNA cytology (approximately 5% or less), consider nodule surveillance. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient. If molecular diagnostics are technically inadequate or not done, then repeat FNA. c Estimated risk of malignancy is 6%–18% exclusive of noninvasive follicular thyroid neoplasm with papillary‑like nuclear features (NIFTP). d Based on rapid growth of nodule, imaging, physical examination, age, clinical history of radiation, and family history. e The order of the treatment options does not indicate preference. f Total thyroidectomy may be considered for Hürthle cell neoplasm (Bethesda IV), history of radiation exposure, or contralateral lobe lesions. g TI‑RADS (https://www.jacr.org/article/S1546‑1440(17)30186‑2/pdf) or ATA (https://www.ncbi.nlm.nih. gov/pmc/articles/PMC4739132/pdf/thy.2015.0020.pdf). h Consider second opinion pathology. See PAP‑1 See FOLL‑1 See HÜRT‑1 Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 9. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion THYR‑2 Consider lobectomy or total thyroidectomy (depending on molecular results)b for definitive diagnosis/treatment or Nodule surveillanceg TREATMENTi b The diagnosis of follicular carcinoma or Hürthle cell carcinoma requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Molecular diagnostics may be useful to allow reclassification of follicular lesions (ie, follicular neoplasm, AUS, FLUS) as either more or less likely to be benign or malignant based on the genetic profile. If molecular testing suggests papillary thyroid carcinoma, especially in the case of BRAF V600E, see PAP‑1. Molecular diagnostics specifically for medullary thyroid cancer across Bethesda III-VI nodules may identify these specific carcinomas given the challenges of cytology to explicitly identify them (category 2B). If molecular testing, in conjunction with clinical and ultrasound features, predicts a risk of malignancy comparable to the risk of malignancy seen with a benign FNA cytology (approximately 5% or less), consider nodule surveillance. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient. If molecular diagnostics are technically inadequate or not done, then repeat FNA. c Estimated risk of malignancy is 6%–18% exclusive of noninvasive follicular thyroid neoplasm with papillary‑like nuclear features (NIFTP). g TI‑RADS (https://www.jacr.org/article/S1546‑1440(17)30186‑2/pdf) or ATA (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739132/pdf/thy.2015.0020.pdf). i Clinical risk factors, sonographic patterns, and patient preference can help determine whether nodule surveillance or surgery is appropriate. j Alternative term: Suspicious for follicular neoplasm. Estimated risk of malignancy is 15%–40%. Numbers may vary by institution or cytopathologist. Diagnostic categories for FNA results reflect NCI state of the science conference, the Bethesda Classification. Cibas ES, Ali SZ. Thyroid 2017;27:1341‑1346. https:// www.ncbi.nlm.nih.gov/pubmed/29091573. Cytology reports should be interpreted in light of terminology used by local cytopathologists. AUS/FLUSc (Bethesda III) or Follicular neoplasmj (Bethesda IV)b Molecular diagnostics suggestive of malignancy Molecular diagnostics indicate benign lesionb Nodule surveillanceg MOLECULAR DIAGNOSTIC RESULTS Molecular diagnostics not informative or with insufficient or degraded sample Nodule surveillanceg or Consider lobectomy or total thyroidectomy in select situations for definitive diagnosis/treatment or Consider repeat biopsy Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 10. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion FNA RESULTS DIAGNOSTIC PROCEDURES PREOPERATIVE OR INTRAOPERATIVE DECISION‑MAKING CRITERIA PRIMARY TREATMENT Papillary carcinoma or suspicious for papillary carcinoma • Thyroid and neck ultrasound (including central and lateral compartments), if not previously done • CT/MRI with contrast for locally advanced disease or vocal cord paresisa • Consider assessment of vocal cord mobility (ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy)b • Fine-needle aspiration (FNA) for suspicious lateral neck nodesc Indications for total thyroidectomy (any present): • Known distant metastases • Extrathyroidal extension • Tumor 4 cm in diameter • Lateral cervical lymph node metastases or gross central neck lymph node metastases • Poorly differentiated • Consider for prior radiation exposure (category 2B) • Consider for bilateral nodularity Indications for total thyroidectomy or lobectomy, if all criteria present: • No prior radiation exposure • No distant metastases • No lateral cervical lymph node metastases • No extrathyroidal extension • Tumor 1–4 cm in diameter Total thyroidectomy Perform therapeutic neck dissection of involved compartments for clinically apparent/ biopsy‑proven diseased PAP‑1 Active surveillancef with ultrasound or Lobectomye 1 cm ≤1 cm Thyroid and neck ultrasound (including central and lateral compartments), if not previously done No concerning lymph node(s) Concerning lymph node(s) Post- Lobectomy (PAP-2) Manage as ≥1 cm (see pathway above) Total thyroidectomy (category 2B) Postsurgical Evaluation (PAP‑3) Lobectomy (preferred) + isthmusectomy (category 2B) a Use of iodinated contrast is required for optimal cervical imaging using CT; potential delay in radioactive iodine (RAI) treatment will not cause harm. b Vocal cord mobility should be examined in patients if clinical concern for involvement, including those with abnormal voice, surgical history involving the recurrent laryngeal or vagus nerves, invasive disease, or bulky disease of the central neck. Evaluation is imperative in those with voice changes. c Tg washout is useful in diagnosis of lymph node metastases and recommended if cytology is negative. d Routine prophylactic central neck dissection is not indicated in most papillary thyroid cancers. e Posterior location, abutting the trachea or apparent invasion, etc. f Principles of Active Surveillance for Low-Risk Papillary Thyroid Cancer (THYR-D) Post- Lobectomy (PAP-2) Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 11. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP‑2 PRIMARY TREATMENT • Thyroid and neck ultrasound (including central and lateral compartments), if not previously done • Biopsy suspicious lymph nodes or contralateral lesions Any of the following: • Tumor 4 cm • Gross positive resection margins • Gross extra‑thyroidal extension • Confirmed nodal metastasisg • Confirmed contralateral disease • Vascular invasion • Poorly differentiated All of the following: • Negative resection margins • No contralateral lesion • Tumor ≤4 cm in diameter • No suspicious lymph node or • NIFTPh Completion of thyroidectomy • Perform therapeutic neck dissection of involved compartments for clinically apparent/biopsy‑proven disease if not previously done Completion of thyroidectomy or Disease monitoringi (category 2B) Disease monitoringi Consider levothyroxine therapy to keep TSH low or normalj Postsurgical Evaluation (PAP‑3) g Completion of thyroidectomy is not required for incidental small volume pathologic N1A metastases (5 involved nodes with no metastasis 2 mm in largest dimension) PAP‑4. h Formerly called encapsulated follicular variant of PTC, NIFTP has been reclassified and only lobectomy is needed. Ongoing surveillance is recommended. i Measurement of thyroglobulin and antithyroglobulin antibodies may be useful for obtaining a postoperative baseline; however, data to interpret Tg and TgAb in the setting of an intact thyroid lobe are lacking. j Principles of TSH Suppression (THYR‑A). Any of the following: • Lymphatic invasion • Macroscopic multifocal disease (1 cm) Post- lobectomy CLINICAL PRESENTATION Consider levothyroxine therapy to keep thyroid stimulating hormone (TSH) low or normalj Disease Monitoring and Maintenance (PAP‑7) Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 12. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP‑3 POSTSURGICAL EVALUATION No gross residual disease in neck Gross residual disease in neck Resectable Unresectablek Resect, if possible No gross residual disease Gross residual disease • TSH + Tg measurement + antithyroglobulin antibodies (6–12 wks postoperatively) • Iodine-123 or iodine-131l total body radioiodine imaging with TSH stimulation (thyroid hormone withdrawalm) (category 2B) Monitoring of residual disease or Consider External beam RT/intensity- modulated RT (EBRT/IMRT) if disease is threatening vital structuresn RAI uptake present or No RAI imaging performed • Suppress TSH with levothyroxinej • Disease Monitoring and Maintenance (PAP‑7) j Principles of TSH Suppression (THYR‑A). k For bulky, locoregional, viscerally invasive disease or rapid progression, refer to high-volume multidisciplinary institution, including radiation oncology referral. l If considering dosimetry, iodine-131 is the preferred agent. m For contraindications to withdrawal, thyrotropin alfa may be used as an alternative. n Principles of Radiation and RAI Therapy (THYR-C). o Even in the absence of thyroid bed uptake, RAI treatment may be considered. If higher than expected uptake (residual thyroid uptake or distant metastasis), change dose accordingly. p A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. Consideration for Initial Postoperative RAI Therapy After Total Thyroidectomy (PAP‑4) Cross- sectional CT or MRI of neck with contrast For viscerally invasive disease or rapid progression, upfront external beam radiation therapy (EBRT)/ intensity-modulated radiation therapy (IMRT), neoadjuvant therapy may be most appropriaten • TSH + Tg measurement + antithyroglobulin antibodies (6–12 wks postoperatively) • Iodine-123 or iodine-131l total body radioiodine imaging with TSH stimulation (thyroid hormone withdrawalm) (category 2B) RAI uptake present or No RAI imaging performed Monitoring of residual disease or Consider systemic therapy (PAP-9) • Radioiodine treatment (preferred)n • Post‑treatment iodine-131 whole body imaging • TSH-stimulated Tg RAI uptake absento,p RAI uptake absento,p • Radioiodine treatment (preferred) • Post‑treatment iodine-131 whole body imaging • TSH-stimulated Tg • Consider EBRT/IMRTn Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 13. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP‑4 CLINICOPATHOLOGIC FACTORS CONSIDERATION FOR INITIAL POSTOPERATIVE USE OF RAI AFTER TOTAL THYROIDECTOMY RAI not typically recommended (if all present): • Classic papillary thyroid carcinoma (PTC) • Largest primary tumor 2 cm • Intrathyroidal • Unifocal or multifocal (all foci ≤1 cm) • No detectable anti‑Tg antibodies • Postoperative unstimulated Tg 1 ng/mLq • Negative postoperative ultrasound, if doner RAI selectively recommended (if any present): • Detectable anti-Tg antibodies • Largest primary tumor 2–4 cm • High‑risk histologys • Lymphatic invasion • Vascular invasion • Cervical lymph node metastases • Macroscopic multifocality (one focus 1 cm) • Postoperative unstimulated Tg 10 ng/mLq • Microscopic positive margins RAI typically recommended (if any present): • Gross extrathyroidal extensiont • Primary tumor 4 cm • Postoperative unstimulated Tg 10 ng/mLq,u Bulky or 5 positive lymph nodes Radioactive iodine (RAI) ablation is not required in patients with classic PTC who have T1b/T2 (1–4 cm) N0 or NX disease or small‑volume N1a disease (fewer than 5 metastatic lymph nodes with 2 mm of focus of cancer in node), particularly if the postoperative Tg is 1 ng/mL in the absence of interfering anti‑Tg antibodies RAI ablation is recommended when the combination of individual clinical factors (such as the extent of the primary tumor, histology, degree of lymphatic invasion, lymph node metastases, postoperative thyroglobulin, and age at diagnosis) predicts a significant risk of recurrence, distant metastases, or disease‑specific mortality RAI not typically indicated (PAP‑7) RAI Being Considered Based on Clinicopathologic Features (PAP‑5) Known or suspected distant metastases at presentation (PAP‑6) Gross residual disease not amenable to RAI therapy (PAP‑9) For general principles related to radioactive iodine (RAI) therapy, see the Principles of Radiation and Radioactive Iodine Therapy (THYR-C). q Tg values obtained 6–12 weeks after total thyroidectomy. r If preoperative imaging incomplete, consider postoperative ultrasound including central and lateral neck components. s eg, poorly differentiated, tall cell, columnar cell, hobnail variants, diffuse sclerosing, and insular. t Minimal extrathyroidal extension alone likely does not warrant RAI. u Additional cross‑sectional imaging (CT or MRI of the neck with contrast and chest CT with contrast) should be considered to rule out the presence of significant normal thyroid remnant or gross residual disease and to detect clinically significant distant metastases. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 14. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP-5 Clinicopathologic findings prompting consideration for RAI, without gross residual disease or known distant metastasis (PAP‑4) Consider pretreatment neck imagingo,p,v • Disease Monitoring and Maintenance (PAP‑7) • Levothyroxine to appropriate TSH target THYR‑A) RAI BEING CONSIDERED BASED ON CLINICOPATHOLOGIC FEATURES 6–12 weeks post- thyroidectomy Resect clinically significant structural disease if possible RAI therapy indicated based on pathology RAI therapy not indicated based on pathology • RAI therapy for remnant ablation or adjuvant therapyn • Post-treatment iodine-131 imaging (whole body RAI scan)n n Principles of Radiation and RAI Therapy (THYR-C). o Even in the absence of thyroid bed uptake RAI treatment may be considered. If higher than expected uptake (residual thyroid uptake or distant metastasis) change dose accordingly. p A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. v While pre‑ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre‑ablation diagnostic scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI‑avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased glomerular filtration rate (GFR). Patients on dialysis require special handling. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 15. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP-6 Known or suspected distant metastases at presentation or elevated Tg (PAP-4) 6–12 weeks post- thyroidectomy • Appropriate cross‑sectional imaging (CT or MRI with contrast) of known metastatic fociw • Resect clinically significant structural disease if possible 6 weeks following cross-sectional imaging: • Consider 24-hour urine iodine • Consider pretreatment radioiodine diagnostic imaging (iodine-123 or iodine-131) with TSH stimulationn,v,x Confirmed radioiodine- avid tumor or Thyroid remnant uptake only RAI therapyn and post‑treatment imaging (whole body RAI scan)n No uptake KNOWN OR SUSPECTED DISTANT METASTATIC DISEASE n Principles of Radiation and RAI Therapy (THYR-C). v While pre‑ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre‑ablation diagnostic scans based on pathology, postoperative Tg, intraoperative finds, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI‑avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased GFR. Patients on dialysis require special handling. w To evaluate macroscopic metastatic foci for potential alterative therapies (eg, surgical resection, external beam irradiation) to prevent invasion/compression of vital structures or pathologic fracture either as a result of disease progression or TSH stimulation. x Thyrotropin alfa may be used for elderly patients for when prolonged hypothyroidism may be risky. Consider RAI adjuvant therapyn and post‑treatment imaging (whole body RAI scan,n consider PET scan) • Disease Monitoring and Maintenance (PAP‑7) • Levothyroxine to appropriate TSH target THYR‑A) • Disease Monitoring and Maintenance (PAP‑7) • Levothyroxine to appropriate TSH target THYR‑A) Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 16. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP-7 DISEASE MONITORING TREATMENT FINDINGS MANAGEMENT Total thyroidectomy without RAI Total thyroidectomy with RAI Lobectomy • Physical examination • TSH • Neck ultrasound at 6–12 months • Physical examination • TSH • Tg measurement and antithyroglobulin antibodies (Tg ab) at 6–12 weeks • Neck ultrasound at 6–12 months • Physical examination • TSH • Tg measurement and Tg aby • Consider TSH- stimulated RAI whole body scan in high risk patients, patients with previous RAI avid metastases, or patients with abnormal Tg levels, stable or rising Tg ab or abnormal ultrasound Abnormal contralateral nodule or lymph node Abnormal imaging and/or rising Tg Biopsy of suspicious areas (if lymph node, include Tg washings) • Physical examination • TSH (goal lower half normal) • Tg measurement and Tg ab yearly if stable • Neck ultrasound annually, and then every 3–5 years if imaging and Tg/Tg ab stable • See the NCCN Guidelines for Survivorship Biopsy of suspicious areas on imaging (Tg washings) Consider additional imaging (CT neck/ chest), PET, or RAI imaging • Physical examination • TSH (0.1 for 5 years) • Neck ultrasound annually for 5 years, and then less often if imaging and Tg measurement and Tg ab if stable • See the NCCN Guidelines for Survivorship Biopsy of suspicious areas on imaging (Tg washings) Clinical Presentation (PAP-2) Abnormal imaging and/or rising Tg Rising or new Tg ab No evidence of disease No evidence of disease No evidence of disease • Physical examination • TSH (goal lower half normal) • Neck ultrasound annually, and then every 3–5 years if stable • See the NCCN Guidelines for Survivorship y In selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated Tg and consider concomitant diagnostic RAI imaging. Recurrent Disease (PAP-8) or Metastatic Disease (PAP-9) Recurrent Disease (PAP-8) Recurrent Disease (PAP-8) or Metastatic Disease (PAP-9) Consider additional imaging (CT neck/ chest), PET, or RAI imaging Rising or new Tg ab Recurrent Disease (PAP-8) Recurrent Disease (PAP-8) or Metastatic Disease (PAP-9) Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 17. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP‑8 • Rising or newly elevated Tg and negative imaging • Non‑resectable tumors • Non‑radioiodine responsivez Suppress TSH with levothyroxinej Locoregional recurrence Surgery (preferred) if resectablebb and Consider Radioiodine treatment,aa if postoperative radioiodine imaging positive or Disease monitoring for non‑progressive disease that is stable and distant from critical structures or For select patients with unresectable, non–radioiodine‑avid, and progressive disease, consider: EBRT (IMRT/stereotactic body radiation therapy [SBRT])n and/or Systemic therapies (Treatment of Metastatic Disease PAP‑9) or For select patients with limited burden nodal disease, consider local therapies when available (ethanol ablation, radiofrequency ablation [RFA]) Metastatic disease RAI therapy for iodine-avid diseasen and/or Local therapies when availablecc and/or If not amenable to RAI (Treatment of Metastatic Disease PAP‑9) RECURRENT DISEASE Continue surveillance with unstimulated Tg, ultrasound, and other imaging as clinically indicated (PAP‑7) • Progressively rising Tg (basal or stimulated) • Scans (including PET) negative Consider radioiodine therapy with ≥100 mCiaa and Post‑treatment iodine-131 imaging (category 3); additional RAI treatments should be limited to patients who responded to previous RAI therapy (minimum of 6–12 months between RAI treatments) Consider preoperative iodine total body scan aa The administered activity of RAI therapy should be adjusted for pediatric patients. Principles of Radiation and RAI Therapy (THYR-C). bb Preoperative vocal cord assessment, if central neck recurrence. cc Ethanol ablation, cryoablation, RFA, etc. j Principles of TSH Suppression (THYR‑A). n Principles of Radiation and RAI Therapy (THYR-C). z Generally, a tumor is considered iodine‑responsive if follow‑up iodine-123 or low‑dose iodine-131 (1–3 mCi) whole body diagnostic imaging done 6–12 mo after iodine-131 treatment is negative or shows decreasing uptake compared to pre‑treatment scans. It is recommended to use the same preparation and imaging method used for the pre‑treatment scan and therapy. Favorable response to iodine-131 treatment is additionally assessed through change in volume of known iodine‑concentrated lesions by CT/MRI, and by decreasing unstimulated or stimulated Tg levels. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 18. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP‑9 CNS metastases (PAP‑11) TREATMENT OF LOCALLY RECURRENT, ADVANCED, AND/OR METASTATIC DISEASE NOT AMENABLE TO RAI THERAPY j Principles of TSH Suppression (THYR‑A). n Principles of Radiation and RAI Therapy (THYR-C). cc Ethanol ablation, cryoablation, RFA, etc. dd Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B). ee Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. ff Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. Structurally persistent/recurrent locoregional or distant metastatic disease not amenable to RAI therapy Bone metastases (PAP‑10) Soft tissue metastases (eg, lung, liver, muscle) excluding central nervous system (CNS) metastases (see below) • Continue to suppress TSH with levothyroxinej • For advanced, progressive, or threatening disease, genomic testing to identify actionable mutations (including ALK, NTRK, and RET gene fusions), DNA mismatch repair (dMMR), microsatellite instability (MSI), and tumor mutational burden (TMB) • Consider clinical trial • Consider systemic therapy for progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1)dd Other Recommended Regimens ◊ Sorafenib (category 1)dd Useful in Certain Circumstances ◊ Cabozantinib (category 1) if progression after lenvatinib and/ or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab for patients with tumor mutational burden- high (TMB-H) (≥10 mutations/megabase [mut/Mb]) tumors ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriateee,ff • Consider resection of distant metastases and/or EBRT (SBRT/ IMRTn/other local therapiescc when available to metastatic lesions if progressive and/or symptomatic (Locoregional disease PAP‑8) • Disease monitoring is often appropriate in asymptomatic patients with indolent disease assuming no brain metastasisdd (PAP‑7) • Best supportive care, see the NCCN Guidelines for Palliative Care Unresectable locoregional recurrent/ persistent disease Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 19. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP‑10 • Consider surgical palliation and/or EBRT/SBRT/other local therapiescc when available if symptomatic, or asymptomatic in weight‑bearing sites. Embolization prior to surgical resection of bone metastases should be considered to reduce the risk of hemorrhage • Consider embolization or other interventional procedures as alternatives to surgical resection/EBRT/IMRT in select cases • Consider intravenous bisphosphonate or denosumabhh • Disease monitoring may be appropriate in asymptomatic patients with indolent diseasedd (PAP‑7) • Consider systemic therapy for progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1)dd Other Recommended Regimens ◊ Sorafenib (category 1)dd Useful in Certain Circumstances ◊ Cabozantinib (category 1) if progression after lenvatinib and/or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab or patients with TMB-H (≥10 mut/Mb) tumors ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriatedd,ee,ff • Best supportive care, see the NCCN Guidelines for Palliative Care Bone metastases TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYgg ccEthanol ablation, cryoablation, RFA, etc. dd Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B). ee Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. ff Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. gg RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease. hh Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 20. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Papillary Carcinoma NCCN Guidelines Index Table of Contents Discussion PAP‑11 TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYgg • For solitary CNS lesions, either neurosurgical resection or stereotactic radiosurgeryn is preferred or • For multiple CNS lesions, consider radiotherapy, including whole brain radiotherapy or stereotactic radiosurgery,n and/or resection in select cases and/or • Consider systemic therapy for progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1) dd,ii,jj Other Recommended Regimens ◊ Sorafenib (category 1) dd,ii,jj Useful in Certain Circumstances ◊ Cabozantinib (category 1) if progression after lenvatinib and/or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors and/or ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriatedd,ee,ff,hh • Best supportive care, see the NCCN Guidelines for Palliative Care CNS metastases n Principles of Radiation and RAI Therapy (THYR-C). dd Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B). ee Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. ff Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. gg RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease. hh Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. ii After consultation with neurosurgery and radiation oncology, data on the efficacy of lenvatinib or sorafenib for patients with brain metastases have not been established. jj Tyrosine kinase inhibitor (TKI) therapy should be used with caution in otherwise untreated CNS metastases due to bleeding risk. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 21. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion a The diagnosis of follicular carcinoma requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Molecular diagnostics may be useful to allow reclassification of follicular lesions (follicular neoplasm or FLUS) as either more or less likely to be benign or malignant based on the genetic profile. If molecular testing in conjunction with clinical and ultrasound features suggests papillary thyroid carcinoma, especially in the case of BRAF V600E, see PAP‑1. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient. b Use of iodinated contrast is required for optimal cervical imaging using CT; potential delay in RAI treatment will not cause harm. c Vocal cord mobility should be examined in patients if clinical concern for involvement, including those with abnormal voice, surgical history involving the recurrent laryngeal or vagus nerves, invasive disease, or bulky disease of the central neck. Evaluation is imperative in those with voice changes. d Minimally invasive follicular thyroid carcinoma (FTC) is characterized as an encapsulated tumor with microscopic capsular invasion and without vascular invasion. e Formerly called encapsulated follicular variant of PTC, NIFTP has been reclassified and only lobectomy is needed. Ongoing surveillance is recommended. f Principles of TSH Suppression (THYR‑A). g Disease monitoring is preferred in most circumstances. However, there are certain clinical scenarios in which completion of thyroidectomy may be appropriate. FOLL‑1 FNA RESULTS DIAGNOSTIC PROCEDURES PRIMARY TREATMENT Follicular neoplasma (Bethesda IV) (THYR‑1) • Thyroid and neck ultrasound (including central and lateral compartments), if not previously done • CT/MRI with contrast for locally advanced disease or vocal cord paresisb • Consider assessment of vocal cord mobility (ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy)c Benign or NIFTPe Levothyroxine therapy to keep TSH normalf Papillary Carcinoma (PAP‑3) Follicular carcinoma Invasive cancer (widely invasive or encapsulated angioinvasive with ≥4 vessels) Completion of thyroidectomy See Postsurgical Evaluation (FOLL‑2) Encapsulated angioinvasive with 4 vessels or Minimally invasive FTCd Disease monitoring (preferred) or Completion of thyroidectomyg • Consider levothyroxine therapy to keep TSH low or normalf • Disease Monitoring and Management (FOLL‑6) Benign or NIFTPe Disease monitoring • Total thyroidectomy if radiographic evidence or intraoperative findings of extrathyroidal extension or tumor 4 cm in diameter, or patient preference • Perform therapeutic neck dissection of involved compartments for clinically apparent/ biopsy‑proven disease or Lobectomy/ isthmusectomy Papillary Carcinoma (PAP‑3) Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 22. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion FOLL‑2 POSTSURGICAL EVALUATION No gross residual disease in neck Consideration for Initial Postoperative RAI Therapy After Total Thyroidectomy (FOLL‑3) f See Principles of TSH Suppression (THYR‑A). h For bulky, locoregional, viscerally invasive disease or rapid progression, refer to high-volume multidisciplinary institution, including radiation oncology referral. i See Principles of Radiation and RAI Therapy (THYR-C). j If considering dosimetry iodine-131 is the preferred agent. k For contraindications to withdrawal, thyrotropin alfa may be used as an alternative. l Even in the absence of thyroid bed uptake, RAI treatment may be considered. If higher than expected uptake (residual thyroid uptake or distant metastasis), change dose accordingly. m A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. Gross residual disease in neck Resectable Unresectableh Resect, if possible No gross residual disease Gross residual disease • TSH + Tg measurement + antithyroglobulin antibodies (6–12 wks postoperatively) • Iodine-123 or iodine-131j total body radioiodine imaging with TSH stimulation (thyroid hormone withdrawalk) (category 2B) RAI uptake absentl,m Monitoring of residual disease or Consider EBRT/IMRT if disease is threatening vital structuresi • Radioiodine treatment (preferred) • Post‑treatment iodine-131 whole body imaging • TSH-stimulated Tg • Consider EBRT/IMRTi Cross- sectional CT or MRI of neck with contrast • TSH + Tg measurement + antithyroglobulin antibodies (6–12 wks postoperatively) • Iodine-123 or iodine-131j total body radioiodine imaging with TSH stimulation (thyroid hormone withdrawalk) (category 2B) Monitoring of residual disease or Consider systemic therapy (FOLL-8) • Radioiodine treatment (preferred)i • Post‑treatment iodine-131 whole body imaging • TSH-stimulated Tg • Suppress TSH with levothyroxinef • Disease Monitoring and Management (FOLL‑6) RAI uptake present or No RAI imaging performed For viscerally invasive disease or rapid progression, upfront EBRT/IMRT, neoadjuvant therapy may be most appropriatei RAI uptake absentl,m RAI uptake present or No RAI imaging performed Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 23. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion FOLL‑3 CLINICOPATHOLOGIC FACTORS RAI not typically recommended (if all present): • Largest primary tumor 2 cm • Intrathyroidal • No vascular invasion • Clinical N0 • No detectable anti‑Tg antibodies • Postoperative unstimulated Tg 1 ng/mLn • Negative postoperative ultrasound, if doneo RAI not typically indicated Disease Monitoring and Maintenance (FOLL‑6) RAI selectively recommended (if any present): • Largest primary tumor 2–4 cm • Minor vascular invasion (4 foci) • Cervical lymph node metastases • Detectable anti-Tg antibodies • Postoperative unstimulated Tg 10 ng/mLn • Microscopic positive margins RAI recommended (if any present): • Gross extrathyroidal extensionp • Primary tumor 4 cm • Extensive vascular invasion (≥4 foci) • Postoperative unstimulated Tg 10 ng/Ln,q • Bulky or 5 positive lymph nodes Known or suspected distant metastases at presentation Amenable to RAI (FOLL-5) RAI Being Considered (FOLL‑4) CONSIDERATION FOR INITIAL POSTOPERATIVE USE OF RAI AFTER TOTAL THYROIDECTOMY Gross Residual Disease Not Amenable to RAI Therapy (FOLL‑8) RAI ablation is recommended when the combination of individual clinical factors (such as the extent of the primary tumor, histology, degree of lymphatic invasion, lymph node metastases, postoperative thyroglobulin, and age at diagnosis) predicts a significant risk of recurrence, distant metastases, or disease‑specific mortality For general principles related to RAI therapy, see the Principles of Radiation and Radioactive Iodine Therapy (THYR-C) n Tg values obtained 6–12 weeks after total thyroidectomy. o If preoperative imaging incomplete, consider postoperative ultrasound including central and lateral neck components. p Minimal extrathyroidal extension alone likely does not warrant RAI. q Additional cross‑sectional imaging (CT or MRI of the neck with contrast and chest CT with contrast) should be considered to rule out the presence of significant normal thyroid remnant or gross residual disease and to detect clinically significant distant metastases. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 24. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion FOLL‑4 6–12 weeks post‑ thyroidectomy Clinicopathologic findings prompting consideration for RAI, without gross residual disease or known distant metastasis (FOLL‑3) Disease Monitoring and Management (FOLL‑6) Levothyroxine to appropriate TSH target (See THYR‑A) RAI BEING CONSIDERED BASED ON CLINICOPATHOLOGIC FEATURES i Principles of Radiation and RAI Therapy (THYR-C). l Even in the absence of thyroid bed uptake RAI treatment may be considered. If higher than expected uptake (residual thyroid uptake or distant metastasis) change dose accordingly. m A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. t While pre‑ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions the panel recommends selective use of pre‑ablation diagnostic scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI‑avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased GFR. Patients on dialysis require special handling. Resect clinically significant structural disease if possible RAI therapy indicated based on pathology RAI therapy not indicated based on pathology • RAI therapy for remnant ablation or adjuvant therapyi • Post-treatment iodine-131 imaging (whole body RAI scan)i Consider pretreatment neck imagingl,m,t Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 25. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion FOLL‑5 KNOWN OR SUSPECTED DISTANT METASTATIC DISEASE 6–12 weeks post- thyroidectomy Known or suspected distant metastases at presentation or elevated Tg (FOLL‑3) • Appropriate cross‑sectional imaging (CT or MRI with contrast) of known metastatic fociu • Resect clinically significant structural disease if possible Confirmed radioiodine- avid tumor or Thyroid remnant uptake only • See Disease Monitoring and Management (FOLL‑6) • Levothyroxine to appropriate TSH target (THYR‑A) Consider RAI adjuvant therapyi and post‑treatment imaging (whole body RAI scan,i consider PET scan) i Principles of Radiation and RAI Therapy (THYR-C). t While pre‑ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions the panel recommends selective use of pre‑ablation diagnostic scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI‑avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased GFR. Patients on dialysis require special handling. u To evaluate macroscopic metastatic foci for potential alterative therapies (such as surgical resection and/or external beam radiation) to prevent invasion/compression of vital structures or pathologic fracture either as a result of disease progression or TSH stimulation. v Thyrotropin alfa may be used for elderly patients for whom prolonged hypothyroidism may be risky. RAI therapyi and post‑treatment imaging (whole body RAI scan)i 6 weeks following cross-sectional imaging: • Consider 24-hour urine iodine • Consider pretreatment radioiodine diagnostic imaging (iodine-123 or iodine-131) with TSH stimulationi,t,v No uptake Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 26. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion Recurrent Disease (FOLL‑7) or Metastatic Disease (FOLL‑8) FOLL‑6 Postsurgical evaluation (FOLL‑2) Recurrent Disease (FOLL‑7) Recurrent Disease (FOLL‑7) Recurrent Disease (FOLL‑7) or Metastatic disease (FOLL‑8) Recurrent Disease (FOLL‑7) or Metastatic Disease (FOLL‑8) DISEASE MONITORING TREATMENT FINDINGS MANAGEMENT Total thyroidectomy without RAI Total thyroidectomy with RAI Lobectomy • Physical examination • TSH • Neck ultrasound at 6–12 months • Physical examination • TSH • Tg measurement and antithyroglobulin antibodies (Tg ab) at 6–12 weeks • Neck ultrasound at 6–12 months • Physical examination • TSH • Tg measurement and Tg abw • Consider TSH- stimulated RAI whole body scan in high- risk patients, patients with previous RAI avid metastases, or patients with abnormal Tg levels, stable or rising Tg ab or abnormal ultrasound Abnormal contralateral nodule or lymph node Abnormal imaging and/or rising Tg Biopsy of suspicious areas (if lymph node, include Tg washings) • Physical examination • TSH (goal lower half normal) • Tg measurement and Tg ab yearly if stable • Neck ultrasound annually, and then every 3–5 years if imaging and Tg/Tg ab stable • See the NCCN Guidelines for Survivorship Biopsy of suspicious areas on imaging (Tg washings) Consider additional imaging (CT neck/ chest), PET, or RAI imaging • Physical examination • TSH (0.1 for 5 years) • Neck ultrasound annually for 5 years, and then less often if imaging and Tg measurement and Tg ab if stable • See the NCCN Guidelines for Survivorship Biopsy of suspicious areas on imaging (Tg washings) Abnormal imaging and/or rising TG Rising or new Tg ab No evidence of disease No evidence of disease No evidence of disease • Physical examination • TSH (goal lower half normal) • Neck ultrasound annually, and then every 3–5 years if stable • See the NCCN Guidelines for Survivorship w In selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated Tg and consider concomitant diagnostic RAI imaging. Consider additional imaging (CT neck/ chest), PET, or RAI imaging Rising or new Tg ab Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 27. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion FOLL‑7 • Rising or newly elevated Tg and negative imaging • Non‑resectable tumors • Non‑radioiodine responsivex Suppress TSH with levothyroxinef Locoregional recurrence Surgery (preferred) if resectabley and Consider radioiodine treatment,z if postoperative radioiodine imaging positive or Disease monitoring for non‑progressive disease that is stable and distant from critical structures or For select patients with unresectable, non–radioiodine‑avid, and progressive disease, consider: EBRT (IMRT/SBRT)i and/or Systemic therapies (Treatment of Metastatic Disease FOLL‑8) or For select patients with limited burden nodal disease, consider local therapies when available (eg, ethanol ablation, RFA) Metastatic disease RAI therapy for iodine-avid diseasei and/or Local therapies when availableaa and/or If not amenable to RAI FOLL‑8 RECURRENT DISEASE y Preoperative vocal cord assessment, if central neck recurrence. z The administered activity of RAI therapy should be adjusted for pediatric patients. See Principles of Radiation and RAI Therapy (THYR-C). aa Ethanol ablation, cryoablation, RFA, etc. Continue surveillance with unstimulated Tg, ultrasound, and other imaging as clinically indicated (FOLL‑6) Progressively rising Tg (basal or stimulated) Scans (including PET) negative Consider radioiodine therapy with ≥100 mCi and Post‑treatment iodine-131 imaging (category 3); additional RAI treatments should be limited to patients who responded to previous RAI therapy (minimum of 6–12 months between RAI treatments) Consider preoperative iodine total body scan f See Principles of TSH Suppression (THYR‑A). i See Principles of Radiation and RAI Therapy (THYR-C). x Generally, a tumor is considered iodine‑responsive if follow‑up iodine-123 or low‑dose iodine-131 (1–3 mCi) whole body diagnostic imaging done 6–12 mo after iodine-131 treatment is negative or shows decreasing uptake compared to pre‑treatment scans. It is recommended to use the same preparation and imaging method used for the pre‑treatment scan and therapy. Favorable response to iodine-131 treatment is additionally assessed through change in volume of known iodine‑concentrated lesions by CT/MRI, and by decreasing unstimulated or stimulated Tg levels. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 28. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion Unresectable locoregional recurrent/ persistent disease CNS metastases (FOLL‑10) TREATMENT OF LOCALLY RECURRENT, ADVANCED, AND/OR METASTATIC DISEASE NOT AMENABLE TO RAI THERAPY • Consider systemic therapy for progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1)bb Other Recommended Regimens ◊ Sorafenib (category 1)bb Useful in Certain Circumstances ◊ Cabozantinib if progression after lenvatinib and/or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab for patients with tumor mutational burden- high (TMB-H) (≥10 mutations/megabase [mut/Mb]) tumors ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriatecc,dd • Consider resection of distant metastases and/or EBRT (SBRT/ IMRT)i/other local therapiesaa when available to metastatic lesions if progressive and/or symptomatic. (Locoregional disease FOLL‑7) • Disease monitoring is often appropriate in asymptomatic patients with indolent disease assuming no brain metastasis.dd (FOLL‑6) • Best supportive care, see the See NCCN Guidelines for Palliative Care f See Principles of TSH Suppression (THYR‑A). i See Principles of Radiation and RAI Therapy (THYR-C). aa Ethanol ablation, cryoablation, RFA, etc. bb Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR‑B). cc Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. dd Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. FOLL‑8 Structurally persistent/recurrent locoregional or distant metastatic disease not amenable to RAI therapy Bone metastases (FOLL‑9) • Continue to suppress TSH with levothyroxinef • For advanced, progressive, or threatening disease, genomic testing to identify actionable mutations (including ALK, NTRK, and RET gene fusions), dMMR, MSI, and TMB • Consider clinical trial Soft tissue metastases (eg, lung, liver, muscle) excluding CNS metastases (see below) Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 29. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion FOLL‑9 TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYee • Consider surgical palliation and/or EBRT/SBRT/other local therapiesaa when available if symptomatic, or asymptomatic in weight‑bearing sites. Embolization prior to surgical resection of bone metastases should be considered to reduce the risk of hemorrhage • Consider embolization or other interventional procedures as alternatives to surgical resection/EBRT/IMRT in select casesi • Consider intravenous bisphosphonate or denosumabff • Disease monitoring may be appropriate in asymptomatic patients with indolent diseasebb (FOLL‑6) • Consider systemic therapy for progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1)bb Other Recommended Regimens ◊ Sorafenib (category 1)bb Useful in Certain Circumstances ◊ Cabozantinib if progression after lenvatinib and/or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriatebb,cc,dd • Best supportive care, see the NCCN Guidelines for Palliative Care Bone metastases i See Principles of Radiation and RAI Therapy (THYR-C). aa Ethanol ablation, cryoablation, RFA, etc. bb Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR‑B). cc Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. dd Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. ee RAI therapy is an option in some patients with bone metastases and RAI- sensitive disease. ff Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYee Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 30. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Follicular Carcinoma NCCN Guidelines Index Table of Contents Discussion i Principles of Radiation and RAI Therapy (THYR-C). aa Ethanol ablation, cryoablation, RFA, etc. bb Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B). cc Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. dd Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. ee RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease. ff Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. gg After consultation with neurosurgery and radiation oncology; data on the efficacy of lenvatinib or sorafenib for patients with brain metastases have not been established. hh TKI therapy should be used with caution in otherwise untreated CNS metastases due to bleeding risk. FOLL‑10 CNS metastases • For solitary CNS lesions, either neurosurgical resection or stereotactic radiosurgery is preferred or • For multiple CNS lesions, consider radiotherapy,i including whole brain radiotherapy or stereotactic radiosurgery,i and/or resection in select cases and/or • Consider systemic therapy for progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1)bb,gg,hh Other Recommended Regimens ◊ Sorafenib (category 1) bb,gg,hh Useful in Certain Circumstances ◊ Cabozantinib if progression after lenvatinib and/or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors and/or ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriatebb,cc,dd,ff • Best supportive care, see the NCCN Guidelines for Palliative Care TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYee Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 31. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion FNA RESULTS DIAGNOSTIC PROCEDURES PRIMARY TREATMENT Hürthle cell neoplasma (Bethesda IV) THYR‑1 • Thyroid and neck ultrasound (including central and lateral compartments), if not previously done • CT/MRI with contrast for locally advanced disease or vocal cord paresisb • Consider assessment of vocal cord mobility (ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy)c • Total thyroidectomy if radiographic evidence or intraoperative findings of extrathyroidal extension or tumor 4 cm in diameter or patient preference • Perform therapeutic neck dissection of involved compartments for clinically apparent/biopsy‑proven disease or Benign Hürthle cell carcinomae Lobectomy/ isthmusectomy Benign Completion of thyroidectomy Levothyroxine therapy to keep TSH normalf Postsurgical Evaluation (HÜRT‑2) Completion of thyroidectomyg or Disease monitoring (preferred) • Consider levothyroxine therapy to keep TSH low or normalf • Disease Monitoring and Maintenance (HÜRT‑6) Disease monitoring HÜRT‑1 Invasive cancer (widely invasive or encapsulated angioinvasive with ≥4 vessels) Encapsulated angioinvasive with 4 vessels or Minimally invasive Hürthle cell carcinoma (HCC)d aThe diagnosis of Hürthle cell carcinoma requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Consider molecular diagnostics. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient. bUse of iodinated contrast is required for optimal cervical imaging using CT; potential delay in RAI treatment will not cause harm. c Vocal cord mobility should be examined in patients if clinical concern for involvement, including those with abnormal voice, surgical history involving the recurrent laryngeal or vagus nerves, invasive disease, or bulky disease of the central neck. Evaluation is imperative in those with voice changes. dMinimally invasive HCC is characterized as an encapsulated tumor with microscopic capsular invasion and without vascular invasion. eAlso known as oxyphilic, oncocytic, or follicular carcinoma, oncocytic type. f Principles of TSH Suppression (THYR‑A). g Disease monitoring is preferred in most circumstances. However, there are certain clinical scenarios in which completion of thyroidectomy may be appropriate. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 32. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion HÜRT‑2 See Consideration for Initial Postoperative RAI Therapy (HÜRT‑3) f Principles of TSH Suppression (THYR‑A). h For bulky, locoregional, viscerally invasive disease or rapid progression, refer to high-volume multidisciplinary institution, including radiation oncology referral. i If considering dosimetry, iodine-131 is the preferred agent. j Principles of Radiation and RAI Therapy (THYR-C). k For contraindications to withdrawal, thyrotropin alfa may be used as an alternative. l Even in the absence of thyroid bed uptake, RAI treatment may be considered. If higher than expected uptake (residual thyroid uptake or distant metastasis), change dose accordingly. m A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. POSTSURGICAL EVALUATION Gross residual disease in neck Resectable Unresectableh Resect, if possible No gross residual disease Gross residual disease • TSH + Tg measurement + antithyroglobulin antibodies (6–12 wks postoperatively) • Iodine-123 or iodine-131i total body radioiodine imagingi with TSH stimulation (thyroid hormone withdrawalk) (category 2B) Monitoring of residual disease or Consider EBRT/IMRT if disease is threatening vital structuresj • Radioiodine treatment (preferred) • Post‑treatment iodine-131 whole body imaging • TSH-stimulated Tg • Consider EBRT/IMRTj Cross- sectional CT or MRI of neck with contrast • TSH + Tg measurement + antithyroglobulin antibodies (6–12 wks postoperatively) • Iodine-123 or iodine-131i total body radioiodine imaging (category 2B) Monitoring of residual disease or Consider systemic therapy (HÜRT-8) • Radioiodine treatment (preferred)j • Post‑treatment iodine-131 whole body imaging • TSH-stimulated Tg No gross residual disease in neck • Suppress TSH with levothyroxinef • Disease Monitoring and Maintenance (HÜRT‑6) RAI uptake absentp,q RAI uptake present or No RAI imaging performed RAI uptake present or No RAI imaging performed RAI uptake absentl,m For viscerally invasive disease or rapid progression, upfront EBRT/IMRT, neoadjuvant therapy may be most appropriatej Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 33. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion HÜRT‑3 CLINICOPATHOLOGIC FACTORSn RAI not typically recommended (if all present): • Largest primary tumor 2 cm • Intrathyroidal • No vascular invasion • Clinical N0 • No detectable anti‑Tg antibodies • Postoperative unstimulated Tg 1 ng/mLo • Negative postoperative ultrasound, if donep RAI not typically indicated (HÜRT‑6) RAI being considered (HÜRT‑4) CONSIDERATION FOR INITIAL POSTOPERATIVE USE OF RAI AFTER TOTAL THYROIDECTOMY Known or suspected distant metastases at presentation RAI recommended (if any present): • Gross extrathyroidal extensionq • Primary tumor 4 cm • Extensive vascular invasion (≥ 4 foci) • Postoperative unstimulated Tg 10 ng/Lo,r • Bulky or 5 positive lymph nodes Amenable to RAI (See HÜRT‑5) Gross residual disease not amenable to RAI therapy See HÜRT‑8 For general principles related to RAI therapy, see the Principles of Radiation and Radioactive Iodine Therapy (THYR-C) RAI selectively recommended (if any present): • Largest primary tumor 2–4 cm • Minor vascular invasion(4 foci) • Detectable anti-Tg antibodies • Cervical lymph node metastases • Postoperative unstimulated Tg 10 ng/mLo • Microscopic positive margins RAI ablation is recommended when the combination of individual clinical factors (such as the extent of the primary tumor, histology, degree of lymphatic invasion, lymph node metastases, postoperative thyroglobulin, and age at diagnosis) predicts a significant risk of recurrence, distant metastases, or disease‑specific mortality. n A majority of HCC are non–iodine-avid, particularly for high-risk disease that is negative on iodine-123/iodine-131 imaging. A negative post-therapy scan, especially done without SPECT, will likely miss distant structural disease. If Tg is high and/or pathology is high risk, FDG-PET is indicated. o Tg values obtained 6–12 weeks after total thyroidectomy. p If preoperative imaging incomplete, consider postoperative ultrasound including central and lateral neck components. q Minimal extrathyroidal extension alone likely does not warrant RAI. r Additional cross‑sectional imaging (CT or MRI of the neck with contrast and chest CT with contrast) should be considered to rule out the presence of significant normal thyroid remnant or gross residual disease and to detect clinically significant distant metastases. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 34. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion HÜRT‑4 6–12 weeks post‑ thyroidectomy Clinicopathologic findings prompting consideration for RAI, without gross residual disease or known distant metastasis (HÜRT‑3) • Disease Monitoring and Maintenance (HÜRT‑6) • Levothyroxine to appropriate TSH target (THYR‑A) RAI BEING CONSIDERED BASED ON CLINICOPATHOLOGIC FEATURES j Principles of Radiation and RAI Therapy (THYR-C). l Even in the absence of thyroid bed uptake, RAI treatment may be considered. If higher than expected uptake (residual thyroid uptake or distant metastasis), change dose accordingly. m A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. u While pre‑ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre‑ablation diagnostic scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI‑avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased GFR. Patients on dialysis require special handling. Resect clinically significant structural disease if possible RAI therapy indicated based on pathology RAI therapy not indicated based on pathology • RAI therapy for remnant ablation or adjuvant therapyj • Post-treatment iodine-131 imaging (whole body RAI scan)j Consider pretreatment neck imagingl,m,u Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 35. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion HÜRT‑5 KNOWN OR SUSPECTED DISTANT METASTATIC DISEASE 6–12 weeks post‑ thyroidectomy Known or suspected distant metastases at presentation or elevated Tg (HÜRT‑3) • Appropriate cross‑sectional imaging (CT or MRI with contrast) of known metastatic fociv • Resect clinically significant structural disease if possible • Disease Monitoring and Maintenance (HÜRT‑6) • Levothyroxine to appropriate target (THYR‑A) Consider RAI adjuvant therapyj and post‑treatment imaging (whole body RAI scan,j consider PET scan) j Principles of Radiation and RAI Therapy (THYR-C). u While pre‑ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre‑ablation diagnostic scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI‑avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased GFR. Patients on dialysis require special handling. v To evaluate macroscopic metastatic foci for potential alterative therapies (such as surgical resection and/or external beam radiation) to prevent invasion/compression. w Thyrotropin alfa may be used for elderly patients for whom prolonged hypothyroidism may be risky. 6 weeks following cross-sectional imaging: • Consider 24-hour urine iodine • Consider pretreatment radioiodine diagnostic imaging (iodine-123 or iodine-131) with TSH stimulationj,u,w Confirmed radioiodine- avid tumor or Thyroid remnant uptake only No uptake • RAI therapyj and post‑treatment imaging (whole body RAI scan)j Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 36. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion DISEASE MONITORING TREATMENT FINDINGS MANAGEMENT Recurrent Disease (HÜRT‑7) or Metastatic Disease (HÜRT‑8) HÜRT‑6 xIn selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated Tg and consider concomitant diagnostic RAI imaging. Postsurgical Evaluation (HÜRT‑2) Recurrent disease (HÜRT‑7) Recurrent Disease (HÜRT‑7) Recurrent Disease (HÜRT‑7) or Metastatic Disease (HÜRT‑8) Recurrent Disease (HÜRT‑7) or Metastatic Disease (HÜRT‑8) Total thyroidectomy without RAI Total thyroidectomy with RAI Lobectomy • Physical examination • TSH • Neck ultrasound at 6–12 months • Physical examination • TSH • Tg measurement and antithyroglobulin antibodies (Tg ab) at 6–12 weeks • Neck ultrasound at 6–12 months • Physical examination • TSH • Tg measurement and Tg abx • Consider TSH- stimulated RAI whole body scan in high- risk patients, patients with previous RAI avid metastases, or patients with abnormal Tg levels, stable or rising Tg ab or abnormal ultrasound Abnormal contralateral nodule or lymph node Abnormal imaging and/or rising Tg Biopsy of suspicious areas (if lymph node, include Tg washings) • Physical examination • TSH (goal lower half normal) • Tg measurement and Tg ab yearly if stable • Neck ultrasound annually, and then every 3–5 years if imaging and Tg/Tg ab stable • See the NCCN Guidelines for Survivorship Biopsy of suspicious areas on imaging (Tg washings) Consider additional imaging (CT neck/ chest), PET, or RAI imaging • Physical examination • TSH (0.1 for 5 years) • Neck ultrasound annually for 5 years, and then less often if imaging and Tg measurement and Tg ab if stable • See the NCCN Guidelines for Survivorship Biopsy of suspicious areas on imaging (Tg washings) Abnormal imaging and/or rising TG Rising or new Tg ab No evidence of disease No evidence of disease No evidence of disease • Physical examination • TSH (goal lower half normal) • Neck ultrasound annually, and then every 3–5 years if stable • See the NCCN Guidelines for Survivorship Consider additional imaging (CT neck/ chest), PET, or RAI imaging Rising or new Tg ab Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 37. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion HÜRT‑7 • Rising or newly elevated Tg and negative imaging • Non‑resectable tumors • Non‑radioiodine responsivey Suppress TSH with levothyroxinef Locoregional recurrence Surgery (preferred) if resectableaa and Consider radioiodine treatment,j if postoperative radioiodine imaging positive or Disease monitoring for non‑progressive disease that is stable and distant from critical structures or For select patients with unresectable, non–radioiodine‑avid, and progressive disease, consider: EBRT (IMRT/SBRT)j and/or Systemic therapies (Treatment of Metastatic Disease HÜRT‑8) or For select patients with limited burden nodal disease, consider local therapies when available (eg, ethanol ablation, RFA) Metastatic disease RAI therapy for iodine-avid diseasej and/or Local therapies when availablebb and/or HÜRT‑8 if not amenable to RAI RECURRENT DISEASE f Principles of TSH Suppression (THYR‑A). j Principles of Radiation and RAI Therapy (THYR-C). y Generally, a tumor is considered iodine‑responsive if follow‑up iodine-123 or low‑dose iodine-131 (1–3 mCi) whole body diagnostic imaging done 6–12 mo after iodine-131 treatment is negative or shows decreasing uptake compared to pre‑treatment scans. It is recommended to use the same preparation and imaging method used for the pre‑treatment scan and therapy. Favorable response to iodine-131 treatment is additionally assessed through change in volume of known iodine‑concentrated lesions by CT/MRI, and by decreasing unstimulated or stimulated Tg levels. z The administered activity of RAI therapy should be adjusted for pediatric patients. Principles of Radiation and RAI Therapy (THYR-C). aa Preoperative vocal cord assessment, if central neck recurrence. bb Ethanol ablation, cryoablation, RFA, etc. Continue surveillance with unstimulated Tg, ultrasound, and other imaging as clinically indicated (HÜRT‑6) • Progressively rising Tg (basal or stimulated) • Scans (including PET) negative Consider radioiodine therapy with ≥100 mCiz and Post‑treatment iodine-131 imaging (category 3); additional RAI treatments should be limited to patients who responded to previous RAI therapy (minimum of 6–12 months between RAI treatments) Consider preoperative iodine total body scan Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 38. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion HÜRT‑8 Unresectable locoregional recurrent/ persistent disease Soft tissue metastases (eg, lung, liver, muscle) excluding CNS metastases (see below) CNS metastases (HÜRT‑10) TREATMENT OF LOCALLY RECURRENT, ADVANCED, AND/OR METASTATIC DISEASE NOT AMENABLE TO RAI THERAPY • Consider systemic therapy for progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1)cc Other Recommended Regimens ◊ Sorafenib (category 1)cc Useful in Certain Circumstances ◊ Cabozantinib if progression after lenvatinib and/or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriatedd,ee • Consider resection of distant metastases and/or EBRT (SBRT/ IMRT)j/other local therapiesbb when available to metastatic lesions if progressive and/or symptomatic (Locoregional disease, HÜRT‑7) • Disease monitoring is often appropriate in asymptomatic patients with indolent disease assuming no brain metastasiscc (HÜRT‑6) • Best supportive care, see the NCCN Guidelines for Palliative Care f Principles of TSH Suppression (THYR‑A). j Principles of Radiation and RAI Therapy (THYR-C). bb Ethanol ablation, cryoablation, RFA, etc. cc Kinase inhibitor therapy may not be approriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B). dd Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. ee Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. Structurally persistent/ recurrent locoregional or distant metastatic disease not amenable to RAI therapy Bone metastases (HÜRT‑9) • Continue to suppress TSH with levothyroxinef • For advanced, progressive, or threatening disease, genomic testing to identify actionable mutations (including ALK, NTRK, and RET gene fusions), dMMR, MSI, and TMB • Consider clinical trial Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 39. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion • Consider surgical palliation and/or EBRT/SBRT/other local therapiesbb when available if symptomatic, or asymptomatic in weight‑bearing sites. Embolization prior to surgical resection of bone metastases should be considered to reduce the risk of hemorrhage • Consider embolization or other interventional procedures as alternatives to surgical resection/EBRT/IMRT in select casesj • Consider intravenous bisphosphonate or denosumabgg • Disease monitoring may be appropriate in asymptomatic patients with indolent diseaseee (HÜRT‑6) • Consider systemic therapy for progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1)cc Other Recommended Regimens ◊ Sorafenib (category 1)cc Useful in Certain Circumstances ◊ Cabozantinib if progression after lenvatinib and/or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriatecc,dd,ee • Best supportive care, see the NCCN Guidelines for Palliative Care Bone metastases TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYff HÜRT‑9 j Principles of Radiation and RAI Therapy (THYR-C). bb Ethanol ablation, cryoablation, RFA, etc. cc Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B). dd Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. ee Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. ff RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease. gg Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 40. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Hürthle Cell Carcinoma NCCN Guidelines Index Table of Contents Discussion • For solitary CNS lesions, either neurosurgical resection or stereotactic radiosurgeryj is preferred or • For multiple CNS lesions, consider radiotherapy,j including whole brain radiotherapyj or stereotactic radiosurgery,j and/or resection in select cases • Consider systemic therapy For progressive and/or symptomatic disease Preferred Regimens ◊ Lenvatinib (category 1)cc,hh,ii Other ◊ Sorafenib (category 1) cc,hh,ii Useful in Certain Circumstances ◊ Cabozantinib if progression after lenvatinib and/or sorafenib ◊ Larotrectinib or entrectinib for patients with NTRK gene fusion-positive advanced solid tumors ◊ Selpercatinib or pralsetinib for patients with RET-fusion positive tumors ◊ Pembrolizumab for patients with TMB-H (≥10 mut/Mb) tumors and/or ◊ Dabrafenib/trametinib for patients with BRAF V600E mutation that has progressed following prior treatment with no satisfactory alternative treatment options ◊ Other therapies are available and can be considered for progressive and/or symptomatic disease if clinical trials or other systemic therapies are not available or appropriatecc,dd,ee,gg • Best supportive care, see the NCCN Guidelines for Palliative Care CNS metastases TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPYdd j Principles of Radiation and RAI Therapy (THYR-C). bb Ethanol ablation, cryoablation, RFA, etc. cc Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy (THYR‑B). dd Commercially available small‑molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive], or dabrafenib [BRAF positive] [all are category 2A]) can be considered if clinical trials are not available or appropriate. ee Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. gg Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. hh After consultation with neurosurgery and radiation oncology; data on the efficacy of lenvatinib or sorafenib for patients with brain metastases have not been established. ii TKI therapy should be used with caution in otherwise untreated CNS metastases due to bleeding risk. HÜRT‑10 Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 41. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Medullary Carcinoma NCCN Guidelines Index Table of Contents Discussion MEDU‑1 CLINICAL PRESENTATION PRIMARY TREATMENT Medullary thyroid carcinoma on FNA by cytology or molecular diagnostics Medullary thyroid carcinoma diagnosed after initial thyroid surgery Germline mutation of RET proto‑oncogenea,b a In view of the risks of thyroidectomy in very young children, referral to a surgeon and team experienced in pediatric thyroid surgery is advised. b Evidence of pheochromocytoma should be evaluated and addressed appropriately before proceeding to the next step on the pathway. c Germline mutation should prompt specific mutation testing in subsequent family members and genetic counseling. See Principles of Cancer Risk Assessment and Counseling (THYR-E). d Vocal cord mobility may be examined in patients with abnormal voice, surgical history involving the recurrent laryngeal or vagus nerves, invasive disease, or bulky disease of the central neck. e Having distant metastases does not mean that surgery is contraindicated. f Imaging may be indicated based on high burden of disease, calcitonin 400 pg/mL, or elevated CEA levels. g Prior to germline testing, all patients should be offered genetic counseling either by their physician or a genetic counselor. See Principles of Cancer Risk Assessment and Counseling (THYR-E). • Basal serum calcitonin level • Carcinoembryonic antigen (CEA) • Pheochromocytoma screeningb • Serum calcium • Screen for germline RET proto‑oncogene mutationsc (exons 10, 11, 13–16); genetic counseling may be indicatedg • Thyroid and neck ultrasound (including central and lateral compartments), if not previously done • Consider evaluation of vocal cord mobility (ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy) d • Additional cross-sectional imaging as indicatedf: Consider contrast‑enhanced CT of neck/ chest and liver MRI or 3‑phase CT of livere Consider Ga‑68 DOTATATE PET/CT; if not available consider bone scan and/or skeletal MRI • Total thyroidectomy with bilateral central neck dissection (level VI) • Therapeutic ipsilateral or bilateral modified neck dissection for clinically or radiologically identifiable disease (levels II–V) • Consider prophylactic ipsilateral modified neck dissection for high‑volume or gross disease in the adjacent central neck • Consider therapeutic EBRT/IMRT for grossly incomplete tumor resection when additional attempts at surgical resection have been ruled out • Adjuvant EBRT/IMRT is rarely recommended • Postoperative administration of levothyroxine to normalize TSH 1.0 cm in diameter and unilateral thyroid disease Total thyroidectomy and consider neck dissection (level VI) Management 2–3 Months Postoperative (MEDU‑5) ≥1.0 cm in diameter or bilateral thyroid disease Additional Workup and Management (MEDU‑2) Additional Workup and Primary Treatment (MEDU‑3) DIAGNOSTIC PROCEDURES Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 42. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Medullary Carcinoma NCCN Guidelines Index Table of Contents Discussion MEDU‑2 CLINICAL PRESENTATION ADDITIONAL WORKUP MANAGEMENT Medullary thyroid carcinoma diagnosed after initial thyroid surgeryh • Basal serum calcitonin level • CEA • Screen for germline RET proto‑oncogene mutationsc,i (exons 10, 11, 13–16); genetic counseling may be indicated • Central and lateral neck compartments ultrasound, if not previously done Germline RET mutation identified Germline RET mutation not identified Additional Workup and Primary Treatment (MEDU‑3) Management 2–3 Months Postoperative (MEDU‑5) c Germline mutation should prompt specific mutation testing in subsequent family members and genetic counseling. See Principles of Cancer Risk Assessment and Counseling (THYR-E). h If initial thyroid surgery was less than a total thyroidectomy, additional surgical intervention (eg, completion thyroidectomy ± central neck dissection) may not be necessary unless there is a positive germline RET mutation or radiographic evidence of disease (ie, biopsy‑proven residual neck disease). i Prior to germline testing, all patients should be offered genetic counseling either by their physician or a genetic counselor. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 43. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Medullary Carcinoma NCCN Guidelines Index Table of Contents Discussion MEDU‑3 CLINICAL PRESENTATION ADDITIONAL WORKUP PRIMARY TREATMENT Germline mutation of RET proto- oncogenea,c Multiple endocrine neoplasia (MEN2B) (RET mutations)j MEN2A/Familial medullary thyroid carcinoma (FMTC) (RET mutations)j • Basal serum calcitonin levelk • CEA • Pheochromocytoma screeningb,l • Central and lateral neck compartments ultrasound,m if not previously done • Consider neck CT with contrast if indicated • Basal serum calcitonin levelk • CEA • Pheochromocytoma screeningb,l • Serum calcium + parathyroid hormone (PTH) • Central and lateral neck compartments ultrasound,m if not previously done • Consider neck CT with contrast if indicated • Total thyroidectomy during the first year of life or at diagnosisa • Therapeutic neck dissection as indicated; consider prophylactic bilateral central neck dissection (level VI) • Consider more extensive node dissection (levels II–V) if tumor(s) 0.5 cm in diameter • Postoperative administration of levothyroxine to normalize TSH Management 2–3 Months Postoperative (MEDU‑5) Primary Treatment (MEDU‑4) a In view of the risks of thyroidectomy in very young children, referral to a surgeon and team experienced in pediatric thyroid surgery is advised. b Evidence of pheochromocytoma should be evaluated and treated appropriately before proceeding to the next step on the pathway. c Germline mutation should prompt specific mutation testing in subsequent family members and genetic counseling. See Principles of Cancer Risk Assessment and Counseling (THYR-E). j The timing of prophylactic thyroidectomy generally depends on the aggressiveness of the inherited RET mutation. Codon M918T mutations are considered highest risk and codon 634 and A883F mutations are considered high risk, with MTC usually presenting at a younger age, whereas other RET mutations associated with MEN2A or FMTC are generally moderate risk. Prophylactic thyroidectomy may be delayed in patients with less high-risk RET mutations that have later onset of MTC, provided the annual basal calcitonin measurement is normal, the annual ultrasound is unremarkable, there is no history of aggressive MTC in the family, and the family is in agreement. (Brandi ML, et al. J Clin Endocrinol Metab 2001;86:5658‑5671; and American Thyroid Association Guidelines Task Force. Wells SA Jr, et al. Thyroid 2015;25:567‑610.) k Normal calcitonin ranges have not been established for very young children. l Screening for pheochromocytoma (MEN2A and MEN2B) and hyperparathyroidism (MEN2A) should be performed annually. For some RET mutations (codons 768, 790, 804, or 891), less frequent screening may be appropriate. m In addition to ultrasound, parathyroid imaging may include sestamibi scan with SPECT or 4D-CT depending on institutional practice/protocol. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 44. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Medullary Carcinoma NCCN Guidelines Index Table of Contents Discussion MEDU‑4 CLINICAL PRESENTATION PRIMARY TREATMENT MEN2A/FMTC (RET mutations)a,c,j Measure serum calcium ± PTH No primary hyperparathyroidism Primary hyperparathyroidism • Total thyroidectomy by age 5a,j or when mutation identifieda (if mutation identified at older age) • Therapeutic ipsilateral or bilateral central neck dissection (level VI) if elevated calcitoninn or CEA test or ultrasound identified thyroid or nodal abnormality • Consider prophylactic ipsilateral modified neck dissection if there is high‑volume or gross disease in the adjacent central neck • Consider more extensive lymph node dissection (levels II–V) if tumor(s) 1.0 cm or central node(s) positive • Postoperative administration of levothyroxine to normalize TSH Management 2–3 Months Postoperative (MEDU‑5) • See Primary Treatment as outlined above • During primary operative procedure and parathyroid exploration: If single adenoma, excise If multiglandular disease, autotransplant or leave the equivalent mass of one normal parathyroid gland Consider cryopreservation of parathyroid tissue Management 2–3 Months Postoperative (MEDU‑5) a In view of the risks of thyroidectomy in very young children, referral to a surgeon and team experienced in pediatric thyroid surgery is advised. c Germline mutation should prompt specific mutation testing in subsequent family members and genetic counseling. See Principles of Cancer Risk Assessment and Counseling (THYR-D 2 of 2). j The timing of prophylactic thyroidectomy generally depends on the aggressiveness of the inherited RET mutation. Codon M918T mutations are considered highest risk and codon 634 and A883F mutations are considered high risk, with MTC usually presenting at a younger age, whereas other RET mutations associated with MEN2A or FMTC are generally moderate risk. Prophylactic thyroidectomy may be delayed in patients with less high-risk RET mutations that have later onset of MTC, provided the annual basal calcitonin measurement is normal, the annual ultrasound is unremarkable, there is no history of aggressive MTC in the family, and the family is in agreement. (Brandi ML, et al. J Clin Endocrinol Metab 2001;86:5658‑5671; and American Thyroid Association Guidelines Task Force. Wells SA Jr, et al. Thyroid 2015;25:567‑610.) n Prophylactic neck dissection may not be required if serum calcitonin is less than 40 ng/mL, because lymph node metastases are unlikely with minor calcitonin elevations in this setting. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 45. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Medullary Carcinoma NCCN Guidelines Index Table of Contents Discussion MEDU‑5 MANAGEMENT 2–3 MONTHS POSTOPERATIVE DISEASE MONITORINGp • Basal calcitonin • CEA Detectable basal calcitonin or Elevated CEA Basal calcitonin undetectable and CEA within reference rangeo • Neck ultrasound • If calcitonin ≥150 pg/mL, CT or MRI with contrast of neck, liver, and chest • Consider bone scan and MRI of axial skeleton in patients with very elevated calcitonin levels Disease monitoring Imaging positive or symptomatic disease Imaging negative and asymptomatic • Serum calcitonin, CEA every 6–12 mo • Additional studies or more frequent testing based on calcitonin/CEA doubling timer FDG PET/CT or Ga‑68 DOTATATE or MRI with contrast of the neck, chest, abdomen with liver protocol • No additional imaging required if calcitonin and CEA stable • Annual serum calcitonin, CEA • Consider central and lateral neck compartments ultrasound • Additional studies or more frequent testing if significantly rising calcitonin or CEAr • No additional imaging required if calcitonin and CEA stable • For MEN2B or MEN2A, annual biochemical screenings for pheochromocytoma and hyperparathyroidism (MEN2A)q Positive result Negative result Positive result Negative result Recurrent or Persistent Disease (MEDU‑6 and MEDU‑7) Continue disease monitoring or Consider cervical reoperation, if primary surgery incomplete Recurrent or Persistent Disease (MEDU‑6 and MEDU‑7) Continue disease monitoring o The likelihood of significant residual disease with an undetectable basal calcitonin is very low. p NCCN Guidelines for Survivorship. q See page PHEO‑1 from the NCCN Guidelines for Neuroendocrine and Adrenal Tumors. r It is unlikely that there will be radiographic evidence of disease when calcitonin is less than 150 pg/mL. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 46. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Medullary Carcinoma NCCN Guidelines Index Table of Contents Discussion MEDU‑6 RECURRENT OR PERSISTENT LOCOREGIONAL DISEASE Locoregional Recurrent or Persistent Disease; Distant Metastases (MEDU‑7) s Increasing tumor markers, in the absence of structural disease progression, are not an indication for treatment with systemic therapy. t Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy in Advanced Thyroid Carcinoma (THYR‑B). u Treatment with systemic therapy is not recommended for increasing calcitonin/CEA alone. v Only health care professionals and pharmacies certified through the vandetanib Risk Evaluation and Mitigation Strategy (REMS) program, a restricted distribution program, will be able to prescribe and dispense the drug. w Genomic testing including TMB or RET somatic genotyping in patients who are germline wild-type or germline unknown. TREATMENT • Surgical resection is the preferred treatment modality • EBRT/IMRT can be considered for unresectable disease or, less commonly, after surgical resection • Consider systemic therapys for unresectable disease that is symptomatic or progressing by RECIST criteriat,u Preferred Regimens ◊ Vandetanibv (category 1) ◊ Cabozantinib (category 1) ◊ Selpercatinib (RET mutation-positive)w ◊ Pralsetinib (RET mutation-positive)w Useful in Certain Circumstances ◊ Pembrolizumab (TMB-H [≥10 mut/Mb])w • Disease monitoring Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 47. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Medullary Carcinoma NCCN Guidelines Index Table of Contents Discussion MEDU‑7 RECURRENT OR PERSISTENT DISEASE DISTANT METASTASES Asymptomatic disease Symptomatic disease or Progressiont • Systemic therapy or clinical trial Preferred Regimens ◊ Vandetanib (category 1)x ◊ Cabozantinib (category 1)x ◊ Selpercatinib (RET mutation-positive)w ◊ Pralsetinib (RET mutation-positive)w Other Recommended Regimens ◊ Consider other small‑molecule kinase inhibitorsy ◊ Dacarbazine (DTIC)‑based chemotherapyz Useful in Certain Circumstances ◊ Pembrolizumab (TMB-H [≥10 mut/Mb])w • EBRT/IMRT for local symptoms • Consider intravenous bisphosphonate or denosumabaa therapy for bone metastases • Consider palliative resection, ablation (eg, RFA, embolization, other regional therapy), or other regional treatment • Best supportive care, see the NCCN Guidelines for Palliative Care Progressive disease, see pathway below sIncreasing tumor markers, in the absence of structural disease progression, are not an indication for treatment with systemic therapy. t Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. Principles of Kinase Inhibitor Therapy in Advanced Thyroid Carcinoma (THYR‑B). uTreatment with systemic therapy is not recommended for increasing calcitonin/CEA alone. v Only health care professionals and pharmacies certified through the vandetanib Risk Evaluation and Mitigation Strategy (REMS) program, a restricted distribution program, will be able to prescribe and dispense the drug. wGenomic testing including TMB or RET somatic genotyping in patients who are germline wild-type or germline unknown. xClinical benefit can be seen in both sporadic and familial MTC. y While not FDA-approved for treatment of medullary thyroid cancer, other commercially available small‑molecule kinase inhibitors (such as sorafenib, sunitinib, lenvatinib, or pazopanib) can be considered if clinical trials or preferred systemic therapy options are not available or appropriate, or if the patient progresses on preferred systemic therapy options. zDoxorubicin/streptozocin alternating with fluorouracil/dacarbazine or fluorouracil/dacarbazine alternating with fluorouracil/streptozocin. aaDenosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk. • Disease monitoring • Consider resection (if possible), ablation (eg, RFA, embolization, other regional therapy) • Systemic therapys if not resectable and progressing by RECIST criteriat,u Preferred Regimens ◊ Vandetanibt,v (category 1) ◊ Cabozantinib (category 1) ◊ Selpercatinib (RET mutation-positive)w ◊ Pralsetinib (RET mutation-positive)w Useful in Certain Circumstances ◊ Pembrolizumab (TMB-H [≥10 mut/Mb])w Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 48. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Anaplastic Carcinoma NCCN Guidelines Index Table of Contents Discussion FNA OR CORE BIOPSY FINDINGa DIAGNOSTIC PROCEDURES Anaplastic thyroid carcinoma (ATC) • CBC with differential • Comprehensive chemistry • TSH • Neck ultrasound • CT with contrast of head, neck, chest, abdomen, pelvis • Laryngoscopy, including evaluation of vocal cord mobility • Fluorodeoxyglucose (FDG) PET/CT or MRI • In case of airway invasion, bronchoscopy • Molecular testing for actionable mutationsb ESTABLISH GOALS OF THERAPYc • Expedient consultation with multidisciplinary management team • Discuss prognosis • Discuss risks/benefits of treatment options • Discuss palliative care options including airway management a Consider core or open biopsy if FNA is “suspicious” for ATC or is not definitive. Morphologic diagnosis combined with immunohistochemistry is necessary to exclude other entities such as poorly differentiated thyroid cancer, medullary thyroid cancer, squamous cell carcinoma, and lymphoma. b Molecular testing should include BRAF, NTRK, ALK, RET, MSI, dMMR, and tumor mutational burden. c Preoperative evaluations need to be completed as quickly as possible and involve integrated decision-making in a multidisciplinary team and with the patient. Consider referral to multidisciplinary high‑volume center with expertise in treating ATC. d Staging (ST‑1). STAGEd Stage IVC (metastatic disease)c ANAP‑3 ANAP‑1 Stage IVA or IVBa,c (locoregional disease) ANAP‑2 Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 49. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Anaplastic Carcinoma NCCN Guidelines Index Table of Contents Discussion STAGEd R0/R1 resectione achieved (usually as incidentally discovered, very small ATC) Adjuvant EBRT/IMRTf with radiosensitizing chemotherapyg when clinically appropriate EBRT/IMRTf with chemotherapyg when clinically appropriate or Consider molecularly targeted neoadjuvant therapyh for borderline resectable disease when safe to do so Surgery can be reconsidered after neoadjuvant therapy depending on response Stage IVA or IVBa,c (locoregional disease) Total thyroidectomy with therapeutic lymph node dissection Resectable Unresectablee a Consider core or open biopsy if FNA is “suspicious” for ATC or is not definitive. Morphologic diagnosis combined with immunohistochemistry is necessary to exclude other entities such as poorly differentiated thyroid cancer, medullary thyroid cancer, squamous cell carcinoma, and lymphoma. c Preoperative evaluations need to be completed as quickly as possible and involve integrated decision-making in a multidisciplinary team and with the patient. Consider referral to multidisciplinary high‑volume center with expertise in treating ATC. d Staging (ST‑1). e Resectability for locoregional disease depends on extent of involved structures, potential morbidity, and mortality associated with resection. In most cases, there is no indication for a debulking surgery. Staging (ST‑1) for definitions of R0/R1/R2. f Principles of Radiation and RAI Therapy (THYR-C). g Adjuvant/Radiosensitizing Chemotherapy Regimens for Anaplastic Thyroid Carcinoma (ANAP‑A [1 of 3]). h Regimens that may be used for neoadjuvant therapy include dabrafenib/trametinib for BRAF V600E mutations; selpercatinib or pralsetinib for RET-fusion positive tumors; and larotrectinib or entrectinib for patients with NTRK gene fusion-positive tumors. TREATMENT Incomplete (R2 resection) ANAP‑2 Disease Monitoring and Management (ANAP-3) EBRT/IMRTf with chemotherapyg when clinically appropriate Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 50. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Anaplastic Carcinoma NCCN Guidelines Index Table of Contents Discussion ANAP‑3 b Molecular testing should include BRAF, NTRK, ALK, RET, MSI, dMMR, and tumor mutational burden. d Staging (ST‑1). i Consider dabrafenib/trametinib if BRAF V600E mutation positive (Subbiah V, et al. J Clin Oncol 2018;36:7‑13); larotrectinib or entrectinib if NTRK gene fusion positive (Drilon A, et al. N Engl J Med 2018;378:731‑739; Doebele RC, et al. Lancet Oncol 2020;21:271-282); selpercatinib or pralsetinib if RET fusion positive (Wirth L, et al. Presented at the Annual Meeting of the European Society for Medical Oncology in Barcelona, Spain; September 27-October 1, 2019. Oral presentation.); or pembrolizumab for TMB-H (Marabelle A, et al. Presented at the Annual Meeting of ESMO in Barcelona, Spain; September 30, 2019). j Consider use of intravenous bisphosphonates or denosumab. Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk. k Systemic Therapy Regimens for Metastatic Disease (ANAP-A [2 of 3]). DISEASE MONITORING AND MANAGEMENT • Cross‑sectional imaging (CT or MRI with contrast) of brain, neck, chest, abdomen, and pelvis at frequent intervals as clinically indicated • Consider FDG PET/CT 3–6 months after initial therapy • Continued disease monitoring if no evidence of disease (NED) • Palliative locoregional radiation therapy • Local lesion control (eg, bone,j brain metastases) • Second‑line systemic therapyk or clinical trial • Best supportive care, see the NCCN Guidelines for Palliative Care Stage IVCd Aggressive therapy Palliative care • Total thyroidectomy with therapeutic lymph node dissection if resectable (R0/R1) • Consider tracheostomy • Locoregional radiation therapy • Systemic therapy (See ANAP‑A [2 of 3]) • Molecular testing for actionable mutationsi if not previously doneb • Consider clinical trial • Palliative locoregional radiation therapy • Local lesion control with surgery or radiation (eg, bone,j brain metastases) • Consider tracheostomy • NCCN Guidelines for Central Nervous System Cancers • Best supportive care METASTATIC DISEASE TREATMENT Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 51. 1 Bible KC,Kebebew E, Brierley J, et al. 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2021;31:337- 386. Adjuvant/Radiosensitizing Chemotherapy Regimens1 Other Recommended Regimens Paclitaxel/carboplatin Paclitaxel 50 mg/m2 , carboplatin AUC 2 IV Weekly Docetaxel/doxorubicin Docetaxel 20 mg/m2 IV, doxorubicin 20 mg/m2 IV Weekly Paclitaxel 30–60 mg/m2 IV Weekly Docetaxel 20 mg/m2 IV Weekly Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Anaplastic Carcinoma NCCN Guidelines Index Table of Contents Discussion ANAP‑A 1 OF 3 Systemic Therapies for Metastatic Disease ANAP-A (2 of 3) SYSTEMIC THERAPY Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 52. Paclitaxel8 60–90 mg/m² IV or 135–200mg/m² Weekly Every 3–4 weeks Doxorubicin8 20 mg/m² IV or 60–75 mg/m² IV Weekly Every 3 weeks Paclitaxel/carboplatin1 (category 2B) Paclitaxel 60–100 mg/m2 , carboplatin AUC 2 IV or Paclitaxel 135–175 mg/m2 , carboplatin AUC 5–6 IV Weekly Every 3–4 weeks Docetaxel/doxorubicin1 (category 2B) Docetaxel 60 mg/m2 IV, doxorubicin 60 mg/m2 IV (with pegfilgrastim) or Docetaxel 20 mg/m2 IV, doxorubicin 20 mg/m2 IV Every 3–4 weeks Weekly Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Anaplastic Carcinoma NCCN Guidelines Index Table of Contents Discussion ANAP‑A 2 OF 3 SYSTEMIC THERAPY Systemic Therapy Regimens for Metastatic Disease Preferred Regimens Dabrafenib/trametinib2 (BRAF V600E mutation positive) Dabrafenib 150 mg PO and Trametinib 2 mg PO Twice daily Once daily Larotrectinib3 (NTRK gene fusion positive) 100 mg PO Twice daily Entrectinib4 (NTRK gene fusion positive) 600 mg PO Once daily Pralsetinib5 (RET fusion positive) 400 mg PO Once daily Selpercatinib6 (RET fusion positive) 120 mg PO (50 kg) or 160 mg PO (≥50 kg) Twice daily Other Recommended Regimens Useful in Certain Circumstances Doxorubicin/cisplatin8 Doxorubicin 60 mg/m² IV, cisplatin 40 mg/m² IV Every 3 weeks Pembrolizumab7 (TMB-H [≥10 mut/Mb]) 200 mg IV or 400 mg IV Every 3 weeks Every 6 weeks References Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 53. Version 3.2022, 11/01/22© 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Version 3.2022 Thyroid Carcinoma – Anaplastic Carcinoma NCCN Guidelines Index Table of Contents Discussion 1 Smallridge RC, Ain KB, Asa SL, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2012;22:1104-1139. 2 Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600‑mutant anaplastic thyroid cancer. J Clin Oncol 2018;36:7‑13. 3 Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion‑positive cancers in adults and children. N Engl J Med 2018;378:731‑739. 4 Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271-282. 5 Subbiah V, Hu MI, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting; May 29-31, 2020. 6 Wirth L, Sherman E, Drilon A, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET-altered thyroid cancers. Presented at the Annual Meeting of the European Society for Medical Oncology; September 27-October 1, 2019; Barcelona, Spain. Oral presentation. 7 Marabelle A, Fakih MG, Lopez J, et al. Association of tumor mutational burden with outcomes in patients with select advanced solid tumors treated with pembrolizumab in KEYNOTE-158. Presented at the Annual Meeting of the European Society for Medical Oncology; September 30, 2019; Barcelona, Spain. 8 Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2021;31:337- 386. ANAP‑A 3 OF 3 SYSTEMIC THERAPY REFERENCES Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 54. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion PRINCIPLES OF THYROID‑STIMULATING HORMONE (TSH) SUPPRESSION THYR‑A • Because TSH is a trophic hormone that can stimulate the growth of cells derived from thyroid follicular epithelium, the use of levothyroxine to maintain low TSH levels is considered optimal in treatment of patients with papillary, follicular, or Hürthle cell carcinoma. However, data are lacking to permit precise specification of the appropriate serum levels of TSH. In general, patients with known structural residual carcinoma or at high risk for recurrence should have TSH levels maintained below 0.1 mU/L Disease‑free patients at low risk for recurrence should have TSH levels maintained either slightly below or slightly above the lower limit of the reference range. For low‑risk patients with biochemical evidence but no structural evidence of disease (eg, Tg positive, but imaging negative), maintain TSH levels at 0.1–0.5 mU/L. • Patients who remain disease free for several years should have their TSH levels maintained within the reference range (0.5–2 mU/L). Given the potential toxicities associated with TSH‑suppressive doses of levothyroxine—including cardiac tachyarrhythmias (especially in the elderly) and bone demineralization (particularly in post‑menopausal women) as well as frank symptoms of thyrotoxicosis—the risks and benefits of TSH‑suppressive therapy must be balanced for each individual patient. Patients whose TSH levels are chronically suppressed should be counseled to ensure adequate daily intake of calcium (1200 mg/day) and vitamin D (1000 IU). Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 55. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion THYR‑B PRINCIPLES OF KINASE INHIBITOR THERAPY IN ADVANCED THYROID CARCINOMA1‑7 • Oral kinase inhibitors demonstrate clinically significant activity in randomized, placebo‑controlled clinical trials in locally recurrent unresectable and metastatic medullary thyroid cancer (MTC) and in radioiodine‑refractory differentiated thyroid cancer (DTC). • When considering kinase inhibitor therapy for individual patients, several factors should be considered. Kinase inhibitor therapy can be associated with improved progression‑free survival, but is not curative. Kinase inhibitor therapy is expected to cause side effects that may have a significant effect on quality of life. The natural history of MTC and DTC is quite variable with rates of disease progression ranging from a few months to many years. • The pace of disease progression should be factored into treatment decisions. Patients with very indolent disease who are asymptomatic may not be appropriate for kinase inhibitor therapy, particularly if the side effects of treatment will adversely affect the patient’s quality of life, whereas patients with more rapidly progressive disease may benefit from kinase inhibitor therapy, even if they have drug‑induced side effects. • Optimal management of kinase inhibitor side effects is essential. Where available, guidelines outlining the management of the dermatologic, hypertensive, and gastrointestinal side effects of kinase inhibitors can be used; side effects have been fatal. In addition, dose modification may be required, including dose holds and dose reductions. • Molecular testing has been shown to be beneficial when making targeted therapy decisions, particularly related to drug therapies or clinical trial participation. In addition, the presence of some mutations may have prognostic importance. 1 Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double‑blind phase III trial. J Clin Oncol 2012;30:134‑141. 2 Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine‑refractory, locally advanced or metastatic differentiated thyroid cancer: a randomized, double‑blind, phase 3 trial. Lancet 2014;384:319‑328. 3 Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013;31:3639‑3646. 4 Burtness B, Anadkat M, Basti S, et al. NCCN Task Force Report: Management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Canc Netw 2009;7 Suppl 1:S5‑S21. 5 Brose MS, Frenette CT, Keefe SM, Stein SM. Management of sorafenib‑related adverse events: a clinician’s perspective. Semin Oncol 2014;41 Suppl 2:S1‑S16. 6 Carhill AA, Cabanillas ME, Jimenez C, et al. The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring. J Clin Endocrinol Metab 2013;98:31‑42. 7 Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine‑refractory thyroid cancer. N Engl J Med 2015;372:621‑630. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 56. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion THYR‑C 1 OF 5 PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY IODINE-131 ADMINISTRATION General Principles Patients may be withdrawn from thyroid hormone to allow adequate elevation of TSH (30 mU/l),1 or prepared using two consecutive daily intramuscular injections of thyrotropin alfa for initial iodine-131 ablation of post-surgical gland remnant and/or treatment of locoregional residual or recurrent disease. • Preparation with hormone withdrawal: duration of time off thyroid hormone depends on the extent of thyroidectomy and approach to hormone replacement in the initial postoperative setting. Because of the half-life of endogenous thyroid hormone, 4–6 weeks are required for clearance following total thyroidectomy. Consequently, if no thyroid hormone is given following total thyroidectomy in an euthyroid patient, endogenous TSH levels should be sufficiently elevated (30) in 3–6 weeks. • Thyroid hormone withdrawal is preferred for most patients with distant metastatic disease based on the likelihood of augmentation of the delivered radiation dose. While thyrotropin alfa is not FDA-approved for treatment of distant metastases, it has been studied in this setting in retrospective cohorts and its use may be considered for patients unable to withdraw from thyroid hormone based on comorbidities and other clinical considerations.2,3 • Regardless of preparation method, an iodine-restricted diet is recommended for 10–14 days prior to iodine-131 therapy. A review of recent clinical history is advised to confirm the absence of recent iodinated contrast administration, amiodarone therapy over the past year, or long-acting iodine contaminants. Dietary supplements such as fish oil and daily multivitamins containing iodine should also be withheld over this period. Most common contrast media for CT require a 2-month period between contrast administration and iodine scintigraphy for adequate washout. If available, a 24-hour urine collection should be performed to confirm a normal free iodine (100 mcg/24 h) prior to the initiation of the iodine-restricted diet. The diet involves a 10- to 14-day reduction in intake of iodized salt, seafood, and dairy products with the intention of optimizing the sensitivity of diagnostic examinations and the efficacy of potential therapies that may follow. Excellent resource information can be found at ThyCa.org and LIDLifeCommunity.org. • Documentation of negative pregnancy test or infertility status is required for female patients of reproductive age prior to administration of radioiodine therapy. • Adherence to all local, state, and national regulatory guidelines including signed informed consent and signed written directive from an authorized user should be confirmed. • Written guidelines for minimizing exposure to others should be provided for patient signature, as per national and state regulatory requirements. • Pre-treatment radioiodine imaging may be considered and a post-treatment iodine-131 whole body scan should be performed in all cases. • Pre-therapy whole body scans may be obtained using 2–4 mCi iodine-123 or 1–2 mCi iodine-131. Iodine-123 avoids stunning and has favorable imaging characteristics. Low activity (1–3 mCi) iodine-131 minimizes stunning and has a longer physical half-life that will permit delayed imaging to improve lesion detection while permitting dosimetry in cases where dose maximization is considered. If iodine-131 is utilized then the time between the scanning and therapy doses should ideally by 48 to 72 hours to avoid “stunning” from the diagnostic dose. • Patients with high (1000 mCi) cumulative lifetime administered activities should be monitored for myelosuppression and potential long-term toxicities, and although rare this should be considered in a risk-benefit analysis for use of RAI, as with any other therapy. References Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 57. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion THYR‑C 2 OF 5 PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY IODINE-131 ADMINISTRATION Administered Activity See special circumstances below for pediatric dose adjustment. • Remnant ablation: 30–50 mCi ◊ If RAI ablation is used in T1b/T2 (1–4 cm), clinical N0 disease, in the absence of other adverse pathologic, laboratory, or imaging features, 30–50 mCi of iodine-131 is recommended (category 1) following either thyrotropin alfa stimulation or thyroid hormone withdrawal. This dose of 30–50 mCi may also be considered (category 2B) for patients with T1b/T2 (1–4 cm) with small- volume N1a disease (fewer than 5 lymph node metastases 2 mm in diameter) and for patients with primary tumors 4 cm, clinical M0 with minor extrathyroidal extension.4,5 • Adjuvant therapy: 50–150 mCi ◊ For higher likelihood of residual disease based on operative pathology or pretherapy radioiodine scan • Treatment of known disease 100–200 mCi ◊ For proven unresectable or metastatic disease based on pathology or pretherapy radioiodine scan Dosimetry can be used to determine maximal dose at high-volume centers for documented nonresectable, large-volume, iodine- concentrating, residual, or recurrent disease. Generally, the maximum 48-hour whole-body dose should not exceed ~80 mCi to avoid pulmonary fibrosis in the case of diffuse lung metastases, and the bone marrow retention maximum should not exceed ~120 mCi at 48 hours.1 Special Circumstances • Pediatric patients: Chest imaging using non-contrast CT prior to treatment to assess for lung metastases Weight-based dose adjustment for pediatric patients assuming routine dosing for 70 kg adult (ie, a 150 mCi dose for a 70 kg adult would translate to 2.15 mCi/kg for the pediatric patient)6 Special Circumstances • RAI after imaging study or procedure using iodine contrast agent: Wait 2 months to allow for free iodine levels to decrease (100 mcg/24 hours) and allow for optimal RAI uptake7,8 Consider measurement of 24-hour urine iodine to confirm a normal free iodine prior to preparing for dosing. • Breastfeeding patients: Wait 3–6 months after cessation of lactation or with normalization of serum prolactin levels. Complete cessation of breastfeeding after iodine-123 or iodine-131 administration for the current infant. There should be no increased risk to mother or infant for breastfeeding with subsequent births assuming no radioiodine is administered around the subsequent birth/breastfeeding period.9 • Decreased glomerular filtration rate (GFR)/end-stage renal disease (ESRD)/hemodialysis: Special consideration to administered dose, and timing with respect to dialysis to maximize therapeutic effect and minimize non-thyroid uptake/exposure10 Multidisciplinary involvement including close monitoring by radiation safety to coordinate administration, monitoring, and minimization of exposure to others • Patients desiring pregnancy Patients should be counseled to wait at least 6 months after iodine-131 therapy to attempt pregnancy to avoid adverse pregnancy outcomes (such as fetal hypothyroidism, malformation, increased malignancy risk in the child, or fetal demise [with high doses]) related to RAI. For many patients a longer interval before attempting pregnancy may be recommended to confirm disease-free status at 6–12 months post-RAI. In these cases, earlier pregnancy is inadvisable as it would interfere with disease detection and further management. In selective cases when doses are high or other considerations are present, integrating care with reproductive endocrinology/ oncofertility for men and women may be appropriate. References Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 58. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion THYR‑C 3 OF 5 PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY EXTERNAL BEAM RADIATION THERAPY (EBRT) General Principles • The decision to treat and timing of treatment with EBRT for thyroid carcinoma is best made by a multidisciplinary team that must include a radiation oncologist. Evaluation by a radiation oncologist early in the course of treatment for thyroid carcinoma is preferred. The multidisciplinary team should carefully weigh the potential for benefit and the expected acute and chronic toxicity from EBRT when deciding when to incorporate EBRT into an individual patient’s treatment plan. • Consider dental, speech and swallowing, and nutrition evaluation and treatment prior to radiation therapy (RT) to determine if pre-treatment optimization of dental and oral health or gastrostomy placement is appropriate. • Pre-treatment imaging including contrast-enhanced CT or MRI, iodine total body scan/SPECT, and FDG- or DOTATATE-PET can be used to guide radiotherapy volumes. • For patients receiving both RAI and EBRT, the sequence of these therapies should be determined individually for each clinical circumstance. • Conformal radiotherapy techniques including (IMRT) with simultaneous integrated boost (SIB) and image guidance are strongly encouraged in the adjuvant/definitive setting given the potential for reduced toxicity. • For unresected or incompletely resected anaplastic thyroid carcinoma, RT should be started as quickly as possible. Consider a rapid start with 3D RT plan converted to a more conformal RT approach when possible. • For R0 or R1 resection of ATC, adjuvant radiotherapy or chemoradiation should start as soon as the patient is sufficiently recovered from surgery, ideally 2–3 weeks postoperatively. Treatment Volumes • Differentiated, Medullary or Poorly Differentiated (non-anaplastic) Thyroid Cancer – adjuvant or recurrent/persistent RT Little evidence exists for appropriate treatment volumes for thyroid carcinoma. Common practice in published institutional and multi- institutional reports are described. Gross residual disease in the thyroid bed or regional lymph nodes should be included in a gross tumor volume (GTV) (as defined on CT, MRI, and/or FDG-PET). Clinical target volume (CTV) may include the thyroid bed (as identified on preoperative imaging, delineated by surgical clips, any residual disease/thyroid tissue). Regional lymph node levels II–VI can be included if involved or as elective volumes if not evaluated. Dose levels for each are discussed in “Dose and Fractionation” below. GTV should be expanded by 0.5–1.5 cm to CTV. Planning target volume (PTV) margins of 0.3–0.5 cm should be added to CTV, depending on technique and image guidance used. • Anaplastic thyroid carcinoma11-14 GTV includes gross primary disease and involved lymph nodes (determined on contrast-enhanced CT, MRI, and/or FDG-PET, assuming obtaining these studies does not delay start of treatment). High-risk CTV may include involved lymph node regions and postoperative bed in the case of partial or complete debulking surgery. Elective nodal regions may be included in low-dose CTV if extended-field RT is used. GTV should be expanded by 0.5–1.5 cm to CTV. PTV margins of 0.3–0.5 cm should be added to CTV, depending on technique and image guidance used. References Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 59. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion THYR‑C 4 OF 5 PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY EXTERNAL BEAM RADIATION THERAPY (EBRT) Dose and Fractionation Little evidence exists for appropriate treatment volumes for thyroid carcinoma. A wide variety of dose regimens exists in the literature, and the most common practice in published institutional and multi-institutional reports are described here.15-21 The treating radiation oncologist should use clinical judgment to determine the appropriate volumes, doses, and fractionation for each patient. Differentiated, Medullary, or Poorly Differentiated (non-anaplastic) Thyroid Cancer • Adjuvant RT for high-risk disease (after R1 resection) Microscopic disease (thyroid bed, involved resected lymph node regions): 60–66 Gy in 1.8–2 Gy per fraction Elective nodal regions: 50–56 Gy in 1.6–2 Gy per fraction • Salvage RT after R2 resection or inoperable patients Gross disease: 66–70 Gy in 1.8–2 Gy per fraction Microscopic disease (thyroid bed, involved resected lymph node regions): 60–66 Gy in 1.8–2 Gy per fraction Elective nodal regions: 50–56 Gy in 1.6–2 Gy per fraction • Palliative RT of metastases Bony or soft-tissue metastases22 ◊ For patients with oligometastatic disease and good performance status consider higher doses (45–60 Gy) in 1.8–2 Gy daily fractions, or SBRT following principles for treatment of oligometastases ◊ For patients with widely metastatic disease and/or poor performance status limiting life expectancy, consider 8 Gy in 1 fraction; 20 Gy in 5 daily fractions; 30 Gy in 10 daily fractions CNS metastases (NCCN Guidelines for Central Nervous System Cancers BRAIN-C 5 of 8) ◊ ≤4 metastases – consider stereotactic radiosurgery (SRS) either following surgical resection or as monotherapy ◊ Multiple metastases: – Consider enrollment on clinical trial for SRS versus whole brain radiation therapy (WBRT) (with or without hippocampal avoidance) – WBRT – 30 Gy in 10 daily fractions; consider 45 Gy in 1.8 Gy daily fractions for good performance status23,24 Anaplastic Thyroid Cancer • Adjuvant RT after R0 or R1 resection14,25-27 Microscopic disease/high-risk regions: 60–66 Gy in 1.2 Gy twice- daily fractions or 1.8–2 Gy daily fractions26,28 Elective nodal regions can be treated with SIB: 45–54 Gy in 0.8–1.0 Gy twice-daily fractions or 1.6–1.8 Gy once-daily fraction Chemoradiation may be considered on an individual basis.13 • Salvage RT after R2 resection or inoperable patients13,14,26 Gross disease: 66–70 Gy in 1.2 Gy twice-daily fractions or 1.8–2 Gy daily fractions Microscopic disease/high-risk regions: 60–66 Gy in 1.2 Gy twice- daily fractions or 1.8–2 Gy daily fractions12,13 Elective nodal regions can be treated with SIB: 45–54 Gy in 0.8–1.0 Gy twice-daily fractions or 1.6–1.8 Gy once-daily fraction Chemoradiation may be considered on an individual basis.13 • Palliative neck RT 20 Gy in 5 daily fractions, 30 Gy in 10 daily fractions, 45 Gy in 15 daily fractions • Palliative RT of metastases Bony or soft tissue metastases ◊ 8 Gy in 1 fraction; 20 Gy in 5 daily fractions; 30 Gy in 10 daily fractions CNS metastases ◊ Whole brain radiation – 30 Gy in 10 daily fractions (NCCN Guidelines for Central Nervous System Cancers BRAIN-C 5 of 8) References Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 60. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion THYR‑C 5 OF 5 PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY REFERENCES 1 Edmonds CJ, Hayes S, Kermode JC, Thompson BD. Measurement of serum TSH and thyroid hormones in the management of treatment of thyroid carcinoma with radioiodine. Br J Radiol 1977;50:799-807. 2 Klubo-Gwiezdzinska J, Burman KD, Van Nostrand D, et al. Radioiodine treatment of metastatic thyroid cancer: relative efficacy and side effect profile of preparation by thyroid hormone withdrawal versus recombinant human thyrotropin. Thyroid 2012;22:310-317. 3 Tala H, Robbins R, Fagin JA, et al. Five-year survival is similar in thyroid cancer patients with distant metastases prepared for radioactive iodine therapy with either thyroid hormone withdrawal or recombinant human TSH. J Clin Endocrinol Metab 2011;96:2105-2111. 4 Mallick U, Harmer C, Yap B, et al. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med 2012;366:1674-1685. 5 Schlumberger M, Catargi B, Borget I, et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 2012;366:1663-1673. 6 Reynolds JC. Comparison of I-131 absorbed radiation doses in children and adults: A tool for estimating therapeutic I-131 doses in children. Robbins J. Ed., Treatment of Thyroid Cancer in Childhood. Proceedings of a Workshop held Sept 10-11, 1992 at the National Institutes of Health, 1994:127-136. 7 Padovani RP, Kasamatsu TS, Nakabashi CC, et al. One month is sufficient for urinary iodine to return to its baseline value after the use of water-soluble iodinated contrast agents in post-thyroidectomy patients requiring radioiodine therapy. Thryoid 2012;22:926-930. 8 Nimmons GL, Funk GF, Graham MM, Pagedar NA. Urinary iodine excretion after contrast computed tomography scan: implications for radioactive iodine use. JAMA Otolaryngol Head Neck Surg 2013;139:479-482. 9 Stabin MG, Breitz HB. Breast milk excretion of radiopharmaceuticals: mechanisms, findings, and radiation dosimetry. J Nucl Med 2000;41:863-873. 10 Holst JP, Burman KD, Atkins F, et al. Radioiodine therapy for thyroid cancer and hyperthyroidism in patients with end-stage renal disease on hemodialysis. Thyroid 2005;15:1321-1331. 11 Rao SN, Zafereo M, Dadu R, et al. Patterns of treatment failure in anaplastic thyroid carcinoma. Thyroid 2017;27:672-681. 12 Heron DE, Karimpour S, Grigsby PW. Anaplastic thyroid carcinoma: Comparison of conventional radiotherapy and hyperfractionation chemoradiotherapy in two groups. Am J Clin Oncol 2002;25:442-446. 13 Pezzi TA, Mohamed ASR, Sheu T, et al. Radiation therapy dose is associated with improved survival for unresected anaplastic thyroid carcinoma: Outcomes from the National Cancer Data Base. Cancer 2017;123:1653-1661. 14 Park JW, Choi SH, Yoon HI, et al. Treatment outcomes of radiotherapy for anaplastic thyroid cancer. Radiat Oncol J 2018;36:103-113. 15 Romesser PB, Sherman EJ, Shaha AR, et al. External beam radiotherapy with or without concurrent chemotherapy in advanced or recurrent non-anaplastic non-medullary thyroid cancer. J Surg Oncol 2014;110:375-382. 16 Vernat SS, Khalifa J, Sun XS, et al. 10-year locoregional control with postoperative external beam radiotherapy in patients with locally advanced High-Risk Non-Anaplastic Thyroid Carcinoma De Novo or at Relapse, a propensity score analysis. Cancers (Basel) 2019;11:849. 17 Tuttle RM, Rondeau G, Lee NY. A risk-adapted approach to the use of radioactive iodine and external beam radiation in the treatment of well- differentiated thyroid cancer. Cancer Control 2011;18:89-95. 18 Chen PV, Osborne R, Ahn E, et al. Adjuvant external-beam radiotherapy in patients with high-risk well-differentiated thyroid cancer. Ear Nose Throat J 2009;88:E01. 19 Azrif M, Slevin NJ, Sykes AJ, et al. Patterns of relapse following radiotherapy for differentiated thyroid cancer: Implication for target volume delineation. Radiother Oncol 2008;89:105-113. 20 Hu A, Clark J, Payne RJ, et al. Extrathyroidal extension in well-differentiated thyroid cancer: Macroscopic vs microscopic as a predictor of outcome. Arch Otolaryngol Head Neck Surg 2007;133:644-649. 21 Keum KC, Suh YG, Koom WS, et al. The role of postoperative external-beam radiotherapy in the management of patients with papillary thyroid cancer invading the trachea. Int J Radiat Biol Phys 2006;65:474-480. 22 Schlumberger M, Challeton C, De Vathaire F, et al. Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med 1996;37:598-605. 23 McWilliams RR, Giannini C, Hay ID, et al. Management of brain metastases from thyroid carcinoma: a study of 16 pathologically confirmed cases over 25 years. Cancer 2003;98:256-362. 24 Osborne JR, Kondraciuk JD, Rice SL, et al. Thyroid cancer brain metastases: Survival and genomic charactristics of a large tertiary care cohort. Clin Nucl Med 2019;44:544-549. 25 Rao SN, Zafereo M, Dadu R, et al. Patterns of treatment failure in anaplastic thyroid carcinoma. Thyroid 2017;27:672-681. 26 Heron DE, Karimpour S, Grigsby PW. Anaplastic thyroid carcinoma: comparison of conventional radiotherapy and hyperfractionation chemoradiotherapy in two groups. Am J Clin Oncol 2002;25:442-446. 27 Saeed NA, Kelly JR, Deshpande HA, et al. Adjuvant external beam radiotherapy for surgically resected, nonmetastatic anaplastic thyroid cancer. Head Neck 2020;42:1031-1044. 28 Wang Y, Tsang R, Asa S, et al. Clinical outcome of anaplastic thyroid carcinoma treated with radiotherapy of once- and twice-daily fractionation regimens. Cancer 2006;107:1786-1792. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 61. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion PRINCIPLES OF ACTIVE SURVEILLANCE FOR LOW-RISK PAPILLARY THYROID CANCER Definition of Active Surveillance • A treatment plan that involves closely watching a patient’s condition but not giving any treatment unless there are changes in test results that show the condition is getting worse. Evidence for Active Surveillance • There is low quality evidence that active surveillance is an appropriate management option for some patients with low-risk papillary thyroid microcarcinoma (tumor size ≤1 cma), and there are limited data on the role of active surveillance in cancers 1 cm. Active Surveillance should not be used in the following scenariosb: • Tumor characteristics: Aggressive histology such as tall cell variant; invasion of recurrent laryngeal nerve, trachea, or esophagus; visible extrathyroidal extension; regional or distant metastases; tumor near posterior capsule. • Patient characteristics: Unable or unwilling to follow-up for surveillance. • Physician characteristics: Lack of experience and confidence in the use of neck ultrasound. Surveillance Strategy • Neck ultrasound, with inclusion of thyroid and lymph node regions, should be performed every 6 months for 1–2 years and then annually. Transitioning to Surgeryc • Patient preference for converting to surgery is an indication, as well as clinical changes, such as new biopsy-proven lymph node metastases; distant metastases; invasion into recurrent laryngeal nerve, trachea, or esophagus; and, radiologic evidence of extrathyroidal extension. In prior studies, cancer growth by 3 mm in any dimension was also an indication for surgical consultation. a FNA is not routinely recommended in nodules 1 cm with low-risk features. b Determining which patients are candidates for active surveillance involves shared decision making. c Since surgery is the alternative treatment option, surgeons should be involved in discussions on transitioning to surgery. THYR-D Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 62. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN Guidelines Index Table of Contents Discussion See the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic for the following: • Principles of Cancer Risk Assessment and Counseling (EVAL-A) • Pedigree: First-, Second-, and Third-Degree Relatives of Proband (EVAL-B) PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING THYR-E Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 63. Used with permissionof the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. American Joint Committee on Cancer (AJCC) TNM Staging For Thyroid‑Differentiated and Anaplastic Carcinoma (8th ed., 2017) Table 1. Definitions for T, N, M T Primary Tumor TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor ≤2 cm or less in greatest dimension limited to the thyroid T1a Tumor ≤1 cm in greatest dimension limited to the thyroid T1b Tumor 1 cm but ≤2 cm in greatest dimension limited to the thyroid T2 Tumor 2 cm but ≤4 cm in greatest dimension limited to the thyroid T3 Tumor 4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles T3a Tumor 4 cm limited to the thyroid T3b Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size T4 Includes gross extrathyroidal extension beyond the strap muscle T4a Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size T4b Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size Note: All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification). N Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No evidence of locoregional lymph node metastasis N0a One or more cytologically or histologically confirmed benign lymph nodes N0b No radiologic or clinical evidence of locoregional lymph node metastasis N1 Metastasis to regional nodes N1a Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease N1b Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes M Distant Metastasis M0 No distant metastasis M1 Distant metastasis NCCN Guidelines Version 3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion ST‑1 Continued Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 64. Histopathologic Type • Papillarythyroid carcinoma (PTC) Papillary microcarcinoma Follicular variant of PTC Encapsulated variant of PTC Papillary microcarcinoma Columnar cell variant of PTC Oncocytic variant of of PTC • Follicular thyroid carcinoma (FTC), NOS FTC, minimally invasive FTC, encapsulated angioinvasive FTC, widely invasive • Hürthle cell carcinoma • Poorly differentiated thyroid carcinoma (used for insular carcinoma as a subtype of poorly differentiated) • Anaplastic thyroid carcinoma American Joint Committee on Cancer (AJCC) TNM Staging For Thyroid‑Differentiated and Anaplastic Carcinoma (8th ed., 2017) Table 2. AJCC Prognostic Stage Groups Differentiated Under 55 years T N M Stage I Any T Any N M0 Stage II Any T Any N M1 Differentiated 55 Years and Older T N M Stage I T1 N0/NX M0 T2 N0/NX M0 Stage II T1 N1 M0 T2 N1 M0 T3a/T3b Any N M0 Stage III T4a Any N M0 Stage IVA T4b Any N M0 Stage IVB Any T Any N M1 Anaplastic T N M Stage IVA T1‑T3a N0/NX M0 Stage IVB T1‑T3a N1 M0 T3b Any N M0 T4 Any N M0 Stage IVC Any T Any N M1 Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. NCCN Guidelines Version 3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion ST‑2 Continued Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 65. American Joint Committeeon Cancer (AJCC) TNM Staging For Thyroid‑Medullary Carcinoma (8th ed., 2017) Table 3. Definitions for T, N, M T Primary Tumor TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor ≤2 cm or less in greatest dimension limited to the thyroid T1a Tumor ≤1 cm in greatest dimension limited to the thyroid T1b Tumor 1 cm but ≤2 cm in greatest dimension limited to the thyroid T2 Tumor 2 cm but ≤4 cm in greatest dimension limited to the thyroid T3 Tumor ≥4 cm or with extrathyroidal extension T3a Tumor ≥4 cm in greatest dimension limited to the thyroid T3b Tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) T4 Advanced disease T4a Moderately advanced disease; tumor of any size with gross extrathyroidal extension into the nearby tissues of the neck, including subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b Very advanced disease; tumor of any size with extension toward the spine or into nearby large blood vessels, gross extrathyroidal extension invading the prevertebral fascia, or encasing the carotid artery or mediastinal vessels N Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No evidence of locoregional lymph node metastasis N0a One or more cytologically or histologically confirmed benign lymph nodes N0b No radiologic or clinical evidence of locoregional lymph node metastasis N1 Metastasis to regional nodes N1a Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease N1b Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes M Distant Metastasis M0 No distant metastasis M1 Distant metastasis Table 2. AJCC Prognostic Stage Groups T N M Stage I T1 N0 M0 Stage II T2 N0 M0 T3 N0 M0 Stage III T1‑T3 N1a M0 Stage IVA T4a Any N M0 T1‑T3 N1b M0 Stage IVB T4b Any N M0 Stage IVC Any T Any N M1 Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. NCCN Guidelines Version 3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion ST‑3 Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 66. NCCN Guidelines Version3.2022 Thyroid Carcinoma Version 3.2022, 11/01/22 © 2022 National Comprehensive Cancer Network® (NCCN® ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Index Table of Contents Discussion NCCN Categories of Evidence and Consensus Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A unless otherwise indicated. NCCN Categories of Preference Preferred intervention Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability. Other recommended intervention Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes. Useful in certain circumstances Other interventions that may be used for selected patient populations (defined with recommendation). All recommendations are considered appropriate. CAT-1 Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 67. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-1 Discussion Table of Contents Overview…………………………………………………………………...MS-2 Epidemiology ...............................................................................MS-2 Literature Search Criteria and Guidelines Update Methodology ....MS-3 Managing Differentiated Thyroid Carcinoma.................................MS-3 Radiation-Induced Thyroid Carcinoma..........................................MS-3 Differentiated Thyroid Carcinoma…………………………………….MS-3 Clinical Presentation and Diagnosis .............................................MS-3 FNA and Molecular Diagnostic Results.........................................MS-4 Recurrence of Differentiated Thyroid Carcinoma ..........................MS-7 Prognosis ....................................................................................MS-7 Tumor Staging ...........................................................................MS-11 Prognostic Scoring Strategies ....................................................MS-11 Surgical Management of Differentiated Thyroid Carcinoma.........MS-12 Radioactive Iodine—Diagnostics and Treatment.........................MS-14 Assessment and Management After Initial Treatment .................MS-17 Papillary Thyroid Carcinoma…………………………………………MS-21 Surgical Therapy........................................................................MS-21 Radioactive Iodine Therapy........................................................MS-23 Surveillance and Maintenance................................................... MS-24 Recurrent Disease .................................................................... MS-24 Metastatic Disease.................................................................... MS-25 Follicular Thyroid Carcinoma………………………………………..MS-27 Hürthle Cell Carcinoma……………………………………………….MS-28 Medullary Thyroid Carcinoma……………………………………….MS-29 Nodule Evaluation and Diagnosis .............................................. MS-29 Staging ..................................................................................... MS-31 Surgical Management ............................................................... MS-31 Adjuvant RT .............................................................................. MS-33 Persistently Increased Calcitonin............................................... MS-33 Postoperative Management and Surveillance ............................ MS-34 Recurrent or Persistent Disease ................................................ MS-34 Anaplastic Thyroid Carcinoma………………………………………MS-36 Diagnosis.................................................................................. MS-37 Prognosis.................................................................................. MS-37 Treatment ................................................................................. MS-38 References.................................................................................. MS-42 This discussion corresponds to the NCCN Guidelines for Thyroid Carcinoma. Last updated: May 5, 2022. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 68. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-2 Overview Epidemiology Thyroid nodules are approximately four times more common in women than in men. Palpable nodules increase in frequency throughout life, reaching a prevalence of about 5% in the U.S. population for individuals aged 50 years and older having palpable thyroid nodules.1-3 Nodules are even more prevalent when the thyroid gland is examined at autopsy or surgery, or when using ultrasonography; 50% of the thyroids studied have nodules, which are almost always benign.2,4 New nodules develop at a rate of about 0.1% per year, beginning in early life, but they develop at a much higher rate (approximately 2% per year) after exposure to head and neck irradiation.5,6 By contrast, thyroid carcinoma is uncommon. For the U.S. population, the lifetime risk of being diagnosed with thyroid carcinoma is 1.2%.7 It is estimated that approximately 43,800 new cases of thyroid carcinoma will be diagnosed in the United States in 2022.8 As with thyroid nodules, thyroid carcinoma occurs two to three times more often in women than in men. Thyroid carcinoma is currently the seventh most common malignancy diagnosed in women.8 The disease is also diagnosed more often in white North Americans than in African Americans. The main histologic types of thyroid carcinoma are: 1) differentiated (including papillary, follicular, and Hürthle cell); 2) medullary; and 3) anaplastic, which is an aggressive undifferentiated tumor. Of 63,324 patients diagnosed with thyroid carcinoma from 2011 to 2015, 89.8% had papillary carcinoma, 4.5% had follicular carcinoma, 1.8% had Hürthle cell carcinoma, 1.6% had medullary carcinoma, and 0.8% had anaplastic carcinoma.7 A population-based study of data collected by the International Agency for Research on Cancer from 1998 to 2012 showed that the global incidence of papillary thyroid carcinoma (PTC) increased during this time.9 Mortality rates for thyroid carcinoma are, in general, very low. Differentiated thyroid carcinomas usually have an excellent prognosis with 10-year survival rates exceeding 90% to 95%.10 In contrast, anaplastic thyroid carcinoma (ATC) is almost uniformly lethal. However, since differentiated thyroid carcinomas represent more than 95% of all cases, most thyroid carcinoma deaths are from papillary, follicular, and Hürthle cell carcinomas. In 2022, it is estimated that approximately 2230 cancer deaths will occur among persons with thyroid carcinoma in the United States.8 Thyroid carcinoma occurs more often in women; however, mortality rates are lower for younger women.7,11-13 Although the estimated incidence of thyroid carcinoma previously increased by an average of ~5% annually between 2004 and 2013, the incidence rate has more recently stabilized, likely due to more conservative indications for thyroid biopsy and the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).14 Because overall mortality has not dramatically increased since 1975 (1150 vs. 2060 deaths), the previous increase in incidence may reflect, at least in part, earlier detection of subclinical disease (ie, small papillary carcinomas).15-20 However, data show the incidence has increased by varying degrees across all tumor sizes and age groups.21-30 The stable age- and gender-adjusted mortality rate for thyroid carcinoma contrasts distinctly with the declining rates for other solid tumors in adults.31,32 A cohort study of 2000–2016 data from U.S. cancer registries showed an increase in incidence of aggressive PTC.33 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Thyroid Carcinoma address management for the different types of thyroid carcinomas including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinoma. Additional sections in these NCCN Guidelines® include Nodule Evaluation, Principles of TSH Suppression, Principles of Kinase Inhibitor Therapy in Advanced Thyroid Carcinoma, and the American Joint Committee on Cancer (AJCC) staging tables.10 This Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 69. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-3 Discussion text describes the recommendations in the algorithm in greater detail, for example, by including the clinical trial data and other references that support the NCCN Panel’s recommendations in the algorithm. By definition, the NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. Literature Search Criteria and Guidelines Update Methodology Prior to the update of this version of the NCCN Guidelines for Thyroid Carcinoma, an electronic search of the PubMed database was performed to obtain key literature since the previous Guidelines update, using the following search term: thyroid carcinoma. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.34 NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. When citing data and recommendations from other organizations, the terms men, male, women, and female will be used to be consistent with the cited sources. Managing Differentiated Thyroid Carcinoma Managing differentiated (ie, papillary, follicular, Hürthle cell) thyroid carcinoma can be a challenge, because until recently, few prospective randomized trials of treatment have been done.35,36 Most of the information about treatment comes from studies of large cohorts of patients for whom therapy has not been randomly assigned. This accounts for much of the disagreement about managing differentiated carcinoma. Nonetheless, most patients can be cured of this disease when properly treated by experienced physicians and surgeons.37 The treatment of choice is surgery, followed by radioactive iodine (RAI) ablation (iodine-131) in selected patients and thyroxine therapy in most patients. Radiation-Induced Thyroid Carcinoma Exposure to ionizing radiation is the only known environmental cause of thyroid carcinoma and usually causes papillary carcinoma.38 The thyroid glands of children are especially vulnerable to ionizing radiation. A child’s thyroid gland has one of the highest risks of developing cancer of any organ. The thyroid gland is the only organ linked to risk at about 0.10 Gy.5 The risk for radiation-induced thyroid carcinoma is greater in females, certain Jewish populations, and patients with a family history of thyroid carcinoma.39 These data suggest that genetic factors are also important in the development of thyroid carcinoma. Beginning within 5 years of irradiation during childhood, new nodules develop at a rate of about 2% annually, reaching a peak incidence within 30 years of irradiation but remaining high at 40 years.5,6 Adults have a very small risk of developing thyroid carcinoma after exposure to iodine-131.40 After the Chernobyl nuclear reactor accident in 1986, many children and adolescents developed papillary carcinomas after being exposed to iodine-131 fallout.41 It became evident that iodine- 131 and other short-lived iodine-131s were potent thyroid carcinogens in these children, particularly those younger than 10 years when they were exposed.42 Iodine deficiency increases the risk for radiation-induced thyroid cancer.43 Although radiation-induced papillary carcinoma tends to appear more aggressive histologically and to have high recurrence rates, the prognosis for survival is similar to that of spontaneously occurring tumors.44-46 Iodine deficiency is associated with follicular carcinoma and anaplastic carcinomas. Differentiated Thyroid Carcinoma Clinical Presentation and Diagnosis Differentiated (ie, papillary, follicular, Hürthle cell) thyroid carcinoma is usually asymptomatic for long periods and commonly presents as a solitary thyroid nodule. However, evaluating all nodules for malignancy is Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 70. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-4 difficult, because benign nodules are so prevalent and because thyroid carcinoma is so uncommon.1,47,48 Moreover, both benign and malignant thyroid nodules are usually asymptomatic, giving no clinical clue to their diagnosis. About 50% of the malignant nodules are discovered during a routine physical examination, by serendipity on imaging studies, or during surgery for benign disease.49 The other 50% are often first noticed by the patient, usually as an asymptomatic nodule.1,47 Fine-needle aspiration (FNA) with ultrasound guidance is the procedure of choice for evaluating suspicious thyroid nodules.3,48,50 Data show that higher thyroid-stimulating hormone (TSH) levels are associated with an increased risk for differentiated thyroid carcinoma in patients with thyroid nodules, although TSH and thyroglobulin (Tg) do not appear to be useful for screening for thyroid cancer.51-54 Although more than 50% of all malignant nodules are asymptomatic, the pretest probability of malignancy in a nodule increases considerably when signs or symptoms are present.55,56 For example, the likelihood that a nodule is malignant increases about 7-fold if it is very firm, fixed to adjacent structures, rapidly growing, associated with enlarged regional lymph nodes, causes vocal cord paralysis, or symptoms of invasion into neck structures are present.56,57 Family history of thyroid cancer is also indicative of malignancy. If two or more of these features are present, the likelihood of thyroid cancer is virtually assured; however, this is a rare situation.57 A patient’s age and gender also affect the probability of malignancy. Other factors that increase the suspicion of malignancy include: 1) a history of head and neck irradiation; 2) a history of diseases associated with thyroid carcinoma, such as familial adenomatous polyposis (formerly called Gardner syndrome), Carney complex, Cowden syndrome, and multiple endocrine neoplasia (MEN) types 2A or 2B; 3) evidence of other thyroid cancer–associated diseases or syndromes, such as hyperparathyroidism, pheochromocytoma, marfanoid habitus, and mucosal neuromas (suggestive of MEN2B), which make the presence of medullary carcinoma more likely; or 4) the presence of suspicious findings detected by imaging, such as focal fluorodeoxyglucose (FDG) uptake on PET or central hypervascularity, irregular border, and/or microcalcifications on ultrasound.3,58 For recommendations regarding evaluation of a thyroid nodule that is known or suspected on an exam or from incidental imaging in adults, see guidelines published by the American Thyroid Association (ATA).3 In 2015, the ATA updated its guidelines on the management of thyroid nodules and thyroid cancer; its comprehensive guidelines also discuss ultrasound and FNA.3 A statement from the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) committee, which is based on the BI-RADS classification for breast cancer, was published in 2017 and also includes recommendations for management of thyroid nodules based on ultrasound findings.59 A systematic review including 12 studies with 13,000 patients and 14,867 thyroid nodules showed pooled sensitivity values of 0.89 (95% CI, 0.80–0.95) for the ATA guidelines and 0.84 (95% CI, 0.76–0.89) for ACR TI-RADS for risk stratification of thyroid nodules.60 Specificity values were much lower: 0.46 (95% CI, 0.29–0.63) for the ATA guidelines and 0.67 (95% CI, 0.56–0.76) for ACR TI-RADS. FNA and Molecular Diagnostic Results Cytologic examination of an FNA specimen is typically categorized as: category I: nondiagnostic or unsatisfactory biopsy; category II: benign (ie, nodular goiter, colloid goiter, hyperplastic/adenomatoid nodule, Hashimoto’s thyroiditis); category III: atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS); category IV: follicular neoplasm or suspicious for follicular neoplasm (includes Hürthle cell neoplasm); category V: suspicious for malignancy; or category VI: malignancy (includes papillary, medullary, anaplastic, or lymphoma). These diagnostic categories for FNA results reflect the 2017 Bethesda Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 71. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-5 System for Reporting Thyroid Cytopathology.61 As of the 2021 update to the NCCN Guidelines for Thyroid Carcinoma, management recommendations are no longer provided for nodules classified as Bethesda I and Bethesda II. Pathology and cytopathology slides should be reviewed at the treating institution by a pathologist with expertise in the diagnosis of thyroid disorders. Although FNA is a very sensitive test— particularly for papillary carcinoma—false-negative results are sometimes obtained; therefore, a reassuring FNA should not override worrisome clinical or radiographic findings.62,63 Molecular diagnostic testing to detect individual mutations (eg, BRAF V600E, RET/PTC, RAS, PAX8/PPAR [peroxisome proliferator-activated receptor] gamma) or pattern recognition approaches using molecular classifiers may be useful in the evaluation of FNA samples that are indeterminate to assist in management decisions.64-72 The BRAF V600E mutation occurs in about 45% of patients with papillary carcinoma and is the most common mutation.73 Some studies have linked the BRAF V600E mutation to poor prognosis, especially when occurring with TERT promoter mutation.74-77 The choice of the precise molecular test depends on the cytology and the clinical question being asked.78-81 Indeterminate groups include: 1) follicular or Hürthle cell neoplasms (Bethesda IV); and 2) AUS/FLUS (Bethesda III).82-84 The NCCN Panel recommends consideration of molecular diagnostic testing for these indeterminate groups.85,86 Historically, studies have shown that molecular diagnostics do not perform well for Hürthle cell neoplasms.83,87,88 More recently, modern genomic classifiers have shown promise for diagnosis of Hürthle cell-containing specimens, with sensitivity values ranging from 88.9% to 92.9% and specificity values ranging from 58.8% to 69.3% for detecting Hürthle cell cancers.89,90 Molecular diagnostic testing may include multigene assays or individual mutational analysis. In addition to their utility in diagnostics, molecular markers are beneficial for making decisions about targeted therapy options for advanced disease and for informing eligibility for some clinical trials. In addition, the presence of some mutations may have prognostic importance. A minority of panelists expressed concern regarding active nodule surveillance of follicular lesions because they were perceived as potentially pre-malignant lesions with a very low, but unknown, malignant potential if not surgically resected (leading to recommendations for either nodule surveillance or considering lobectomy in lesions classified as benign by molecular testing). Clinical risk factors, sonographic patterns, and patient preference can help determine whether nodule surveillance or surgery is appropriate for these patients. Guidance regarding nodule surveillance from the ATA and the ACR TI-RADS should be followed.3,59 A systematic review including 27 studies that evaluated repeat FNA in AUS/FLUS nodules showed that 48% (95% CI, 43%–54%) of nodules were reclassified as benign, with a negative predictive value (NPV) greater than 96%.91 FNA may be repeated for AUS/FLUS, especially if molecular diagnostics are technically inadequate. Rather than proceeding to immediate surgical resection to obtain a definitive diagnosis for these indeterminate FNA cytology groups (follicular lesions), patients can be followed with nodule surveillance if the application of a specific molecular diagnostic test (in conjunction with clinical and ultrasound features) results in a predicted risk of malignancy that is comparable to the rate seen in cytologically benign thyroid FNAs (approximately ≤5%). It is important to note that the predictive value of molecular diagnostics may be significantly influenced by the pre-test probability of disease associated with the various FNA cytology groups. Furthermore, in the cytologically indeterminate groups, the risk of malignancy from FNA can vary widely between institutions.61,92 Because the published studies have focused primarily on adult patients with thyroid Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 72. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-6 nodules, the diagnostic utility of molecular diagnostics in pediatric patients remains to be defined. Therefore, proper implementation of molecular diagnostics into clinical care requires an understanding of both the performance characteristics of the specific molecular test and its clinical meaning across a range of pre-test disease probabilities.86,93 Additional immunohistochemical studies (eg, calcitonin) may occasionally be required to confirm the diagnosis of medullary carcinoma.94 Hürthle cell neoplasms can sometimes mimic medullary carcinoma cytologically and on frozen section. Sometimes it can be difficult to discriminate between anaplastic carcinoma and other primary thyroid malignancies (ie, medullary carcinoma, thyroid lymphoma) or poorly differentiated cancer metastatic to the thyroid.95 Metastatic renal carcinoma can mimic follicular neoplasm, melanoma can mimic medullary carcinoma, and metastatic lung cancer can mimic anaplastic carcinoma.94 Pathology synoptic reports (protocols), such as those from the College of American Pathologists (CAP), are useful for reporting results from examinations of surgical specimens. The CAP protocol was updated in June 2017 and reflects the 8th edition of the AJCC Staging Manual (see Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland on the CAP website).10,96 Follicular and Hürthle cell carcinomas are rarely diagnosed by FNA, because the diagnostic criterion for these malignancies requires demonstration of vascular or capsular invasion.37,48,62,97 Approximately 15% to 40% of lesions classified as “follicular neoplasm” or “suspicious for follicular neoplasm” are malignant, with risk of malignancy varying by institution, cytopathologist, and whether or not NIFTP is excluded.98,99 Nodules that yield an abundance of follicular cells with little or no colloid are nearly impossible to categorize as benign or malignant on the basis of FNA.100 Repeat FNA will not resolve the diagnostic dilemma. However, molecular diagnostic testing may be useful for follicular cell carcinomas (see FNA Results in the NCCN Guidelines for Thyroid Carcinoma).55,86,101 In some patients with follicular lesions, serum TSH level and thyroid iodine-123 or 99m technetium scanning may identify patients with an autonomously functioning or “hot” nodule who often may be spared surgery, because the diagnosis of follicular adenoma (ie, benign) is highly likely.3,102 Patients who are clinically euthyroid with a low TSH and a hot nodule on thyroid imaging should be evaluated and treated for thyrotoxicosis as indicated even when cytology is suspicious for follicular neoplasm. Those with a hypofunctional (cold or warm) nodule and with suspicious clinical and sonographic features should proceed to surgery (see FNA Results in the NCCN Guidelines for Thyroid Carcinoma).2,3 Those patients with an increased or normal TSH and with cytology suspicious for follicular or Hürthle cell neoplasm should undergo diagnostic lobectomy or total thyroidectomy, depending on patient preference unless molecular diagnostic testing predicts a low risk of malignancy. In patients with follicular or Hürthle cell neoplasm on FNA who are selected for thyroid surgery in order to obtain a definitive diagnosis, total thyroidectomy is recommended for bilateral disease, unilateral disease greater than 4 cm (especially in men), invasive cancer, metastatic cancer, or if the patient prefers this approach. When a diagnosis of thyroid carcinoma is promptly established using FNA, the tumor is often confined to the thyroid or has metastasized only to regional nodes; thus, patients can be cured. However, as many as 5% of patients with papillary carcinoma and up to 10% of those patients with follicular or Hürthle cell carcinoma have tumors that aggressively invade structures in the neck or have produced distant metastases. Such cancers are difficult to cure. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 73. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-7 Recurrence of Differentiated Thyroid Carcinoma Depending on initial therapy and other prognostic variables, up to 30% of patients with differentiated thyroid carcinoma may have tumor recurrences during several decades; 66% of these recurrences occur within the first decade after initial therapy.12 Although not usually fatal, a recurrence in the neck is serious and must be regarded as the first sign of a potentially lethal outcome.103,104 In one large study, central neck recurrences were seen most often in the cervical lymph nodes (74%), followed by the thyroid remnant (20%), and then the trachea or muscle (6%). Of the group with local recurrences, 8% eventually died of cancer.12 Distant metastases were the sites of recurrence in 21% of patients in this cohort, most often (63%) in the lungs alone. Of the patients with distant metastases, 50% died of cancer.12 It is important to recognize that the poor outcomes in this study were probably related to the manner in which the recurrence was diagnosed. In the past, disease recurrence was heralded by symptoms or palpable disease on physical examination, reflecting relatively large-volume disease recurrence. However, tools that are highly sensitive for detecting disease (eg, sensitive Tg assays, high-resolution neck ultrasound) appear to have resulted in earlier detection of disease recurrence, which is now often found in the first 2 to 5 years of follow-up.3,105 These non-palpable, small-volume lymph node recurrences often show little evidence of disease progression over many years and do not appear to be associated with an increase in mortality.106,107 Prognosis Age, Stage, and Sex at Diagnosis Although many factors influence the outcome for patients with papillary and follicular carcinomas, patient age at the time of initial therapy and tumor stage are important.12,108-110 Age is the most important prognostic variable for thyroid cancer mortality. However, thyroid cancer is more aggressive in men. Thyroid carcinoma is more lethal in patients older than 40 years, increasingly so with each subsequent decade of life. The mortality rate increases dramatically after age 60 years. However, tumor recurrence shows a remarkably different behavior with respect to age. Recurrence frequencies are highest (40%) for those younger than 20 years or older than 60 years; recurrence at other ages ensues in only about 20% of patients.12,108-111 This disparity between cancer-related mortality and the frequency of tumor recurrence probably accounts for most of the disagreements among clinicians concerning optimal treatment for patients with differentiated thyroid carcinoma. How clinicians assess the importance of tumor recurrence (as opposed to cancer-specific survival) accounts for much of the debate surrounding the influence of age on the treatment plan for children and young adults. A systematic review including five studies showed that risk of tumor enlargement in patients with PTC undergoing active surveillance was negatively associated with age.112 Children typically present with more advanced disease and have more tumor recurrences after therapy than adults, yet their prognosis for survival is good.113,114 Although the prognosis of children with thyroid carcinoma is favorable for long-term survival (90% at 20 years), the standardized mortality ratio is 8-fold higher than predicted.115 Some clinicians believe that young age imparts such a favorable influence on survival that it overshadows the behavior expected from the characteristics of the tumor. Therefore, they classify most thyroid tumors as low-risk tumors that may be treated with lobectomy alone.116-118 However, most physicians treating the disease believe that tumor stage and its histologic features should be as significant as the patient’s age in determining management.12,113,119,120 Prognosis is less favorable in men than in women, but the difference is usually small.12,118 One study found that gender was an independent prognostic variable for survival and that the risk of death from cancer was about twice as high in men as in women.12 Because of this risk factor, men Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 74. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-8 with thyroid carcinoma—especially those who are older than 40 years— may be regarded with special concern.121 Familial Syndromes Familial, non-medullary carcinoma accounts for about 5% of PTCs and, in some cases, may be clinically more aggressive than the sporadic form.122,123 For patients to be considered as having familial papillary carcinoma, most studies require at least three first-degree relatives to be diagnosed with papillary carcinoma because the finding of cancer in a single first-degree relative may just be a chance event. Microscopic familial papillary carcinoma tends to be multifocal and bilateral, often with vascular invasion, lymph node metastases, and high rates of recurrence and distant metastases.124 Other familial syndromes associated with papillary carcinoma are familial adenomatous polyposis,125 Carney complex (multiple neoplasia and lentiginosis syndrome, which affects endocrine glands),126 and Cowden syndrome (multiple hamartomas).127 The prognosis for patients with all of these syndromes is not different from the prognosis of those with spontaneously occurring papillary carcinoma. Tumor Variables Affecting Prognosis Some tumor features have a profound influence on prognosis.111,128-130 The most important features are tumor histology, primary tumor size, local invasion, necrosis, vascular invasion, BRAF V600E mutation status, and metastases.74,131,132 For example, vascular invasion (even within the thyroid gland) is associated with more aggressive disease and with a higher incidence of recurrence.133-136 The CAP protocol provides definitions of vascular invasion and other terms (see Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland on the CAP website).96 In patients with sporadic medullary carcinoma, a somatic RET oncogene mutation confers an adverse prognosis.137 A meta-analysis including 13 studies showed that PD-L1 expression is associated with lower disease-free survival (DFS) (hazard ratio [HR], 3.37; 95% CI, 2.54–4.48; P .00001) and overall survival (OS) (HR, 2.52; 95% CI, 1.20–5.32; P = .01) in patients with thyroid cancer.138 Another meta-analysis including 15 studies also showed a significant association between PD-L1 expression and lower DFS (HR, 1.90; 95% CI, 1.33–2.70; P .001), but OS was not significantly associated with PD-L1 expression.139 Subgroup analyses showed that the association between PD-L1 expression and DFS was significant for papillary carcinoma (HR, 2.18; 95% CI, 1.08–4.39), but not for poorly differentiated or anaplastic thyroid carcinoma (HR, 1.63; 95% CI, 0.62–4.32). Histology Although survival rates with typical papillary carcinoma are quite good, cancer-specific mortality rates vary considerably with certain histologic subsets of tumors.1 A well-defined tumor capsule, which is found in about 10% of PTCs, is a particularly favorable prognostic indicator. A worse prognosis is associated with anaplastic tumor transformation; tall-cell papillary variants, which have a 10-year mortality of up to 25%; columnar variant papillary carcinoma (a rapidly growing tumor with a high mortality rate); hobnail variant papillary carcinoma, which is associated with increased rates of local and distant metastasis; and diffuse sclerosing variants, which infiltrate the entire gland.37,140-142 NIFTP, formerly known as noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), is characterized by its follicular growth pattern, encapsulation or clear demarcation of the tumor from adjacent tissue with no invasion, and nuclear features of papillary carcinoma.143,144 NIFTP tumors have a low risk for adverse outcomes and, therefore, require less aggressive treatment.144-148 NIFTP was re-classified in 2016 to prevent overtreatment of this indolent tumor type as well as the psychological consequences of a cancer diagnosis on the patient.143,144 A systematic review including 29 studies showed that the pooled prevalence rates of NIFTP within EFVPTC and PTC were 43.5% (95% CI, 33.5%– Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 75. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-9 54.0%) and 4.4% (95% CI, 2.0%–9.0%), respectively, based on the revised 2016 diagnostic criteria.149 CAP updated its protocols with NIFTP in the June 2017 version.96 While molecular diagnostic testing may be useful for diagnosing NIFTP in the future, currently available tests were not validated using NIFTP samples. Studies have shown that NIFTP specimens frequently carry characteristic mutations/alterations including RAS, PAX8/PPARγ, and/or BRAF (with the exception of the aggressive BRAF V600 mutations), differentiating them from papillary subtypes that more frequently show BRAF V600E and RET/PTC alterations.68,150-152 However, multiple studies investigating the performance of molecular diagnostics for this subtype have reported that most thyroid nodules histologically diagnosed as NIFTP are classified as “suspicious” by GEC, possibly leading to more aggressive surgical treatment than is necessary.153,154 Therefore, the validation of molecular diagnostics with NIFTP samples will be necessary to ensure that the tests are accurately classifying these. Follicular thyroid carcinoma is typically a solitary encapsulated tumor that may be more aggressive than papillary carcinoma. It usually has a microfollicular histologic pattern. It is identified as cancer by follicular cell invasion of the tumor capsule and/or blood vessels. The latter has a worse prognosis than capsular penetration alone.155 Many follicular thyroid carcinomas are minimally invasive tumors, exhibiting only slight tumor capsular penetration without vascular invasion. They closely resemble follicular adenomas and are less likely to produce distant metastases or to cause death.156 FNA or frozen section study cannot differentiate a minimally invasive follicular thyroid carcinoma from a follicular adenoma.48,97 Therefore, the tumor is often simply referred to as a “follicular neoplasm” by the cytopathologist (see Nodule Evaluation in the NCCN Guidelines for Thyroid Carcinoma).62 The diagnosis of follicular thyroid carcinoma is assigned only after analysis of the permanent histologic sections—obtained from diagnostic lobectomy or thyroidectomy—shows tumor capsule invasion by follicular cells. Highly invasive follicular thyroid carcinomas are much less common; they are sometimes recognized at surgery by their invasion of surrounding tissues and extensive invasion of blood vessels. Up to 80% of these cancers metastasize, causing death in about 20% of patients, often within a few years of diagnosis.111 The poor prognosis is closely related to older age at diagnosis, advanced tumor stage, and larger tumor size.12 The mortality rates for papillary and follicular thyroid carcinomas are similar in patients of comparable age and disease stage. Patients with either cancer have an excellent prognosis if the tumors are confined to the thyroid, are small, and are minimally invasive. However, patients with either papillary or follicular thyroid carcinoma have far less favorable outcomes if their disease is highly invasive or they develop distant metastases.12,157 When Hürthle (oncocytic) cells constitute most (or all) of the mass of a malignant tumor, the disease is often classified as Hürthle cell carcinoma. Previously considered a variant of follicular thyroid carcinoma, the World Health Organization (WHO) and AJCC reclassified Hürthle cell carcinoma as a separate entity in 2017.10,158 Molecular studies suggest that this tumor may be more similar to papillary than to follicular thyroid carcinomas,159,160 and genotyping revealed that mutational, transcriptional, and copy number profiles of Hürthle cell carcinomas were distinct from papillary and follicular carcinomas, best categorizing it as a unique class of thyroid malignancy.161 Benign and malignant Hürthle cell tumors usually cannot be discriminated by FNA or frozen section examination, although large (4 cm) tumors are more likely to be malignant than smaller ones.162 Similar to follicular thyroid carcinoma, the diagnosis of Hürthle cell carcinoma is only assigned after analysis of the permanent histologic sections—obtained from diagnostic lobectomy or thyroidectomy—shows tumor capsule invasion by Hürthle cells. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 76. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-10 Hürthle cell carcinomas may be aggressive, especially when vascular invasion or large tumors occur in older patients.163,164 In two large series, pulmonary metastases occurred in 25% and 35% of patients with Hürthle cell carcinoma, about twice the frequency of follicular thyroid carcinoma metastases.165-167 In contrast to papillary or follicular carcinomas, iodine- 131 may be not effective in patients with Hürthle cell carcinoma because fewer Hürthle cell carcinomas concentrate iodine-131. In a series of 100 patients with distant metastases, iodine-131 uptake by pulmonary metastases was seen in more than 50% of the follicular (64%) and papillary (60%) carcinomas but in only 36% of Hürthle cell carcinomas.165 In the National Cancer Database report, the 10-year relative survival rates were 85% for follicular carcinomas and 76% for Hürthle cell carcinomas.168 Primary Tumor Size PTCs smaller than 1 cm, termed “incidentalomas” or “microcarcinomas,” are typically found incidentally after surgery for benign thyroid conditions. Their cancer-specific mortality rates are near zero.169 The risk of recurrence in papillary microcarcinomas ranges from 1% to 2% in unifocal papillary microcarcinomas, and from 4% to 6% in multifocal papillary microcarcinomas.170,171 Other small PTCs become clinically apparent. For example, about 20% of microcarcinomas are multifocal tumors that commonly metastasize to cervical lymph nodes. Some researchers report a 60% rate of nodal metastases from multifocal microcarcinomas,172 which may be the presenting feature and also may be associated with distant metastases.169 Otherwise, small (1.5 cm) papillary or follicular carcinomas confined to the thyroid almost never cause distant metastases. Furthermore, recurrence rates after 30 years are one third of those associated with larger tumors; the 30-year cancer-specific mortality is 0.4% compared to 7% (P .001) for tumors 1.5 cm or larger.12 In fact, the prognosis for papillary and follicular thyroid carcinomas is incrementally poorer as tumors increase in size.157,173 There is a linear relationship between tumor size and recurrence or cancer-specific mortality for both papillary and follicular carcinomas.12 Local Tumor Invasion Up to 10% of differentiated thyroid carcinomas invade through the outer border of the gland and grow directly into surrounding tissues, increasing both morbidity and mortality. The local invasion may be microscopic or gross; it can occur with both papillary and follicular carcinomas.12,174 Recurrence rates are two times higher with locally invasive tumors, and as many as 33% of patients with such tumors die of cancer within a decade.12,175 Lymph Node Metastases In one review, nodal metastases were found in 36% of 8029 adults with papillary carcinoma, in 17% of 1540 patients with follicular thyroid carcinoma, and in up to 80% of children with papillary carcinoma.111 An enlarged cervical lymph node may be the only sign of thyroid carcinoma. In these patients, multiple nodal metastases are usually found at surgery.176 The prognostic importance of regional lymph node metastases is controversial.3 However, an analysis of more than 9900 patients in the SEER database found a significant difference in survival at 14 years for those with and without lymph node metastases (79% vs. 82%, respectively).177 Older patients (45 years) with papillary carcinoma and lymph node metastases also have decreased survival.178 A 2012 review by Randolph et al emphasized the correlation between the size and number of metastatic lymph nodes and the risk of recurrence.179 Identification of fewer than 5 sub-cm metastatic lymph nodes was associated with a low risk of recurrence. Conversely, structural disease recurrence rates of more than 20% to 30% were seen in large-volume lymph node metastases (3 cm, or 5–10 involved lymph nodes). Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 77. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-11 Distant Metastases Distant metastases are the principal cause of death from papillary and follicular carcinomas.180,181 About 50% of these metastases are present at the time of diagnosis.111 Distant metastases occur even more often in patients with Hürthle cell carcinoma (35%) and in those patients who are older than 40 years at diagnosis.165,166 Among iodine-123 patients in 13 studies, the sites of reported distant metastases were lung (49%), bone (25%), both lung and bone (15%), and the central nervous system (CNS) or other soft tissues (10%). The main predictors of outcome for patients with distant metastases are patient age, site of distant metastasis, and whether the metastases concentrate iodine-131.165,166,182,183 Although some patients, especially younger ones, with distant metastases survive for decades, about 50% die within 5 years regardless of tumor histology.111 However, some pulmonary metastases are compatible with long-term survival.184 For example, one study found that when distant metastases were confined to the lung, more than 50% of the patients were alive and free of disease at 10 years, whereas no patients with skeletal metastases survived that long.185 The survival rates are highest in young patients with diffuse lung metastases seen only on iodine-131 imaging and not on x-ray.183,185,186 Prognosis is worse with large pulmonary metastases that do not concentrate iodine-131.165,166,182 Tumor Staging The NCCN Guidelines for Thyroid Carcinoma do not use TNM (tumor, node, metastasis) stages as the primary determinant of management. Instead, many characteristics of the tumor and patient play important roles in these NCCN Guidelines. Many specialists in thyroid cancer also follow this paradigm. When treating differentiated thyroid carcinoma, many clinicians place a stronger emphasis on potential morbidity than on mortality (see Surgical Complications in this Discussion). The current 2017 AJCC staging guidelines (8th edition) for thyroid carcinoma may be useful for prognosis (see Table 1 in the NCCN Guidelines for Thyroid Carcinoma).10 Many studies (including those described in this Discussion) have been based on AJCC-TNM staging from earlier editions, such as the 5th edition187 and not the 6th , 7th , or 8th editions.10,188,189 A 2017 study including 1613 patients with resected differentiated thyroid cancer showed that the 8th edition may be superior to the 7th edition for predicting disease- specific survival, since fewer patients were categorized as stage III and IV under the 8th edition staging.190 Prognostic Scoring Strategies Several staging and clinical prognostic scoring strategies use patient age older than 40 years as a major feature to identify cancer mortality risk from differentiated thyroid carcinoma.109,116,188,189,191 These strategies include the EORTC, TNM 7th edition, AMES (Age, Metastases, Extent, and Size), and AGES (Age, tumor Grade, Extent, and Size). All of these strategies effectively distinguish between patients at low and high risk.173 With incrementally worsening MACIS (Metastasis, Age, Completeness of resection, Invasion, and Size) scores of less than 6, 6 to 6.99, 7 to 7.99, and 8+, however, the 20-year survival rates were 99%, 89%, 56%, and 24%, respectively.116 Unfortunately, a study that classified 269 patients with papillary carcinoma according to five different prognostic paradigms found that some patients in the lowest-risk group from each approach died of cancer.119 This is particularly true of classification schemes that simply categorize patients dichotomously as low or high risk.188,192 The AJCC TNM staging approach (see Table 1 in the NCCN Guidelines for Thyroid Carcinoma), which is perhaps the most widely used indicator of prognosis, classifies tumors in all patients younger than 55 years as stage I or stage II, even those with distant metastases. Although it predicts cancer mortality reasonably well,193,194 TNM staging was not established as a predictor of recurrence and therefore does not accurately forecast the recurrences that often Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 78. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-12 occur in patients who developed thyroid carcinoma when they were young. Two studies have shown the poor predictive value of most staging approaches for thyroid carcinoma, including the TNM system.109,195 A three-tiered staging system—low, intermediate, high—that uses clinicopathologic features to risk stratify with regard to the risk of recurrence has been suggested and validated.196-199 This staging system effectively risk stratifies patients with regard to the risk of recurrence, risk of persistent disease after initial therapy, risk of having persistent structural disease, likelihood of achieving remission in response to initial therapy, and likelihood of being in remission at final follow-up. In another approach, emphasis has been placed on evaluation of response to therapy using a dynamic risk assessment approach in which the initial risk estimates are modified during follow-up as additional data are accumulated.200 This allows ongoing re-assessment of risk and allows the management paradigm to be better tailored to realistic estimates of risk that may change substantially over time. Surgical Management of Differentiated Thyroid Carcinoma Ipsilateral Lobectomy Versus Total Thyroidectomy The appropriate extent of thyroid resection—ipsilateral lobectomy versus total thyroidectomy—is very controversial for lower-risk papillary carcinoma. In most clinical settings, decisions about the extent of thyroidectomy should be individualized and done in consultation with the patient.201 Circumstances in which lobectomy is not recommended are detailed in the NCCN Guidelines. This debate reflects the limitations of prognostic scoring118 and the morbidity often associated with total thyroidectomy performed outside of major cancer centers. Patients treated at the Mayo Clinic Cancer Center for low-risk PTCs (MACIS score ≤3.99) had no improvement in survival rates after undergoing procedures more extensive than ipsilateral lobectomy. Thus, the authors concluded that more aggressive surgery was indicated only for those with higher MACIS scores.202 Cancer-specific mortality and recurrence rates after unilateral or bilateral lobectomy were assessed in patients with papillary carcinoma considered to be low risk by AMES criteria.203 No significant differences were found in cancer-specific mortality or distant metastasis rates between the two groups. However, the 20-year frequencies of local recurrence and nodal metastasis after unilateral lobectomy were 14% and 19%, respectively, which were significantly higher (P = .0001) than the frequencies of 2% and 6% seen after bilateral thyroid lobe resection. Hay et al concluded that bilateral thyroid resection is the preferable initial surgical approach for patients with AMES low-risk papillary carcinoma.203 A more recent retrospective multicenter study from Spain that evaluated the 2015 ATA recommendation that low-risk papillary carcinoma between 1 cm and 4 cm could receive lobectomy as clinically indicated found that 57.5% of patients who received total thyroidectomy between 2000 and 2017 would have needed thyroidectomy if they had first undergone lobectomy only.204 Most NCCN Panel Members recommend total thyroidectomy for patients with biopsy-proven papillary carcinoma who have large-volume pathologic N1 metastases (1 or more nodes 3 cm or larger in largest dimension),3 because this procedure is associated with improved DFS.103,120,203,205 Some centers report that patients treated by lobectomy alone have a 5% to 10% recurrence rate in the opposite thyroid lobe.111,202 After lobectomy, these patients also have an overall long-term recurrence rate of more than 30% (vs. 1% after total thyroidectomy and iodine-131 therapy)12 and the highest frequency (11%) of subsequent pulmonary metastases.206 However, in properly selected patients treated with lobectomy alone, recurrence rates may be as low as 4%.44 Higher recurrence rates are also observed with cervical lymph node metastases and multicentric tumors, providing some additional justification for total thyroidectomy.12 Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 79. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-13 However, some prominent thyroid cancer specialists (including some at NCCN Member Institutions) oppose this view and advocate unilateral lobectomy for most patients with papillary and follicular carcinoma based on 1) the low mortality among most patients (ie, those patients categorized as low risk by the AMES and other prognostic classification schemes); and 2) the high complication rates reported with more extensive thyroidectomy.117,191,207 The large thyroid remnant remaining after unilateral lobectomy, however, may complicate long-term follow-up with serum Tg determinations and whole body iodine-131 imaging. Panel members recommend total lobectomy (without RAI ablation) for patients with papillary carcinoma who have incidental small-volume pathologic N1A metastases (5 involved nodes with no metastasis 5 mm, in largest dimension).208 NCCN Panel Members believe that lobectomy alone is adequate treatment for papillary microcarcinomas provided the patient has not been exposed to radiation, has no other risk factors, and has a tumor 1 cm or smaller that is unifocal and confined to the thyroid without vascular invasion (see Primary Treatment in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).3,209-212 Total lobectomy alone is also adequate treatment for NIFTP pathologies (see Tumor Variables Affecting Prognosis, Histology) and minimally invasive follicular thyroid carcinomas (see Primary Treatment in the NCCN Guidelines for Follicular [Thyroid] Carcinoma). However, completion thyroidectomy is recommended for any of the following: tumor larger than 4 cm in diameter, positive resection margins, gross extrathyroidal extension, macroscopic multifocal disease (ie, 1 cm), macroscopic nodal metastases, confirmed contralateral disease, or vascular invasion.3 Note that “gross extrathyroidal extension” refers to spread of the primary tumor outside of the thyroid capsule with invasion into the surrounding structures such as strap muscles, trachea, larynx, vasculature, esophagus, and/or recurrent laryngeal nerve.131,213,214 Completion Thyroidectomy This procedure is recommended when remnant ablation is anticipated or if long-term follow-up is planned with serum Tg determinations and with (or without) whole body iodine-131 imaging. Large thyroid remnants are difficult to ablate with iodine-131.206 Completion thyroidectomy has a complication rate similar to that of total thyroidectomy. Some experts recommend completion thyroidectomy for routine treatment of tumors 1 cm or larger, because approximately 50% of patients with cancers of this size have additional cancer in the contralateral thyroid lobe.174,215-221 In patients with local or distant tumor recurrence after lobectomy, cancer is found in more than 60% of the resected contralateral lobes.218 Miccoli et al studied irradiated children from Chernobyl who developed thyroid carcinoma and were treated by lobectomy; they found that 61% had unrecognized lung or lymph node metastases that could only be identified after completion thyroidectomy.120 In another study, patients who underwent completion thyroidectomy within 6 months of their primary operation developed significantly fewer lymph node and hematogenous recurrences, and they survived significantly longer than did those in whom the second operation was delayed for more than 6 months.219 Surgical Complications The most common significant complications of thyroidectomy are hypoparathyroidism and recurrent laryngeal nerve injury, which occur more frequently after total thyroidectomy.222 Transient clinical hypoparathyroidism postoperatively is common in adults223 and children120,224 undergoing total thyroidectomy. The rates of long-term recurrent laryngeal nerve injury and hypoparathyroidism, respectively, were 3% and 2.6% after total thyroidectomy and 1.9% and 0.2% after subtotal thyroidectomy.225 One study reported hypocalcemia in 5.4% of patients immediately after total thyroidectomy, persisting in only 0.5% of patients 1 year later.226 Another study reported a 3.4% incidence of Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 80. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-14 long-term recurrent laryngeal nerve injury and a 1.1% incidence of permanent hypocalcemia.227 When experienced surgeons perform thyroidectomies, complications occur at a lower rate. A study of 5860 patients found that surgeons who performed more than 100 thyroidectomies a year had the lowest overall complication rate (4.3%), whereas surgeons who performed fewer than 10 thyroidectomies a year had four times as many complications.228 Radioactive Iodine—Diagnostics and Treatment Diagnostic Whole Body Imaging and Thyroid Stunning When indicated, diagnostic whole body iodine-131 imaging is recommended after surgery to assess the completeness of thyroidectomy and to assess whether residual disease is present (see RAI Being Considered Based on Clinicopathologic Features in the NCCN Guidelines for Papillary, Follicular, and Hürthle Cell Carcinoma). However, a phenomenon termed “stunning” may occur when imaging doses of iodine- 131 induce follicular cell damage.229 Stunning decreases uptake in the thyroid remnant or metastases, thus impairing the therapeutic efficacy of subsequent iodine-131.230 To avoid or reduce the stunning effect, the following have been suggested: 1) the use of small doses of iodine-131 (1–2 mCi) or iodine-123 (2–4 mCi); and/or 2) a shortened interval (48–72 hours) between the diagnostic iodine-131 dose and the therapeutic dose. Iodine-123 is more expensive, and smaller iodine-131 doses have reduced sensitivity when compared with larger iodine-131 doses.229-231 In addition, a large thyroid remnant may obscure detection of residual disease with iodine-131 imaging. Some experts recommend that diagnostic iodine-131 imaging be avoided completely with decisions based on the combination of tumor stage and serum Tg.229 Other experts advocate that whole body iodine-131 diagnostic imaging may alter therapy, for example: 1) when unsuspected metastases are identified; or 2) when an unexpectedly large remnant is identified that requires additional surgery or a reduction in RAI dosage to avoid substantial radiation thyroiditis.3,229,232,233 If iodine contrast agent was used with imaging, then RAI should not begin for at least 2 months after the procedure in order to allow for free iodine levels to decrease and thus allow for optimal RAI uptake.234,235 Note that diagnostic imaging is used less often for patients at low risk. A false-negative pretreatment scan is possible and should not prevent use of RAI if otherwise indicated (see Eligibility for Postoperative Radioactive Iodine [RAI] in this Discussion, below). For known or suspected distant metastatic disease, diagnostic whole body iodine-123 or iodine-131 imaging before postoperative RAI may be considered. Eligibility for Postoperative Radioactive Iodine (RAI) The NCCN Panel recommends a selective use approach to postoperative RAI administration. The three general, but overlapping, functions of postoperative RAI administration include: 1) ablation of the normal thyroid remnant, which may help in surveillance for recurrent disease (see below); 2) adjuvant therapy to try to eliminate suspected micrometastases; or 3) RAI therapy to treat known persistent disease. The NCCN Guidelines have three different pathways for postoperative RAI administration based on clinicopathologic factors: 1) RAI typically recommended; 2) RAI selectively recommended; and 3) RAI not typically recommended (see Clinicopathologic Factors in the NCCN Guidelines for Papillary, Follicular, and Hürthle Cell Carcinoma). Postoperative RAI is typically recommended for patients at high risk of having persistent disease remaining after total thyroidectomy and includes patients with any of the following factors: 1) gross extrathyroidal extension; 2) a primary tumor greater than 4 cm; 3) postoperative unstimulated Tg greater than 10 ng/mL; or 4) 6 or more positive lymph nodes or bulky lymph nodes. In the case of follicular or Hürthle cell carcinoma, extensive vascular invasion (≥4 foci) is another indication for postoperative RAI. Postoperative RAI is also frequently recommended for patients with known/suspected distant metastases at presentation (see Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 81. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-15 Clinicopathologic Factors in the NCCN Guidelines for Papillary, Follicular, and Hürthle Cell Carcinoma). Postoperative RAI is selectively recommended for patients who are at greater risk for recurrence with any of the following clinical indications: largest primary tumor 2 to 4 cm, high-risk histology (for papillary carcinoma), lymphatic or vascular invasion, cervical lymph node metastases, macroscopic multifocality (one focus 1 cm), unstimulated postoperative serum Tg (10 ng/mL), or microscopic positive margins.3,236,237 Tg (even quantitative mass spectrometry approaches) are unreliable for detecting structural disease.238 Therefore, RAI is also selectively recommended for patients with detectable anti-Tg antibodies. The NCCN Panel does not routinely recommend RAI for patients with all of the following factors: 1) either unifocal (2 cm) or multifocal classic papillary microcarcinomas (all foci ≤1 cm) confined to the thyroid; 2) no detectable anti-Tg antibodies; and 3) postoperative unstimulated Tg less than 1 ng/mL. RAI would also not be recommended if a postoperative ultrasound was done (eg, if preoperative imaging was incomplete) and was negative. Minimal extrathyroidal extension alone does not warrant postoperative RAI. Guidelines from the ATA list very similar indications for postoperative RAI use and also provide specific guidance regarding the safe use of RAI in the outpatient setting.3,239 Postoperative Administration of RAI Studies show decreased recurrence and disease-specific mortality for populations at intermediate or higher risk when postoperative iodine-131 therapy is administered as part of the initial treatment.12,110,119,240-242 In a study assessing outcomes in 1004 patients with differentiated thyroid carcinoma, tumor recurrence was about 3-fold higher in patients either treated with thyroid hormone alone or given no postoperative medical therapy when compared with patients who underwent postoperative thyroid remnant ablation with iodine-131 (P .001). Moreover, fewer patients developed distant metastases (P .002) after thyroid remnant iodine-131 ablation than after other forms of postoperative treatment. However, this effect is observed only in patients with primary tumors 1.5 cm or larger in diameter.240 Another study of 21,870 intermediate risk patients with differentiated thyroid cancer found that postoperative RAI improved OS (P .001) and was associated with a 29% reduction in the risk of death after adjustment for demographic and clinical factors (HR, 0.71; 95% CI, 0.62–0.82; P .001).242 Some studies have found that remnant ablation had less of a therapeutic effect, perhaps because more extensive locoregional surgery had been done.173 Previously, it was reported that postoperative RAI was associated with decreased OS in patients with stage I thyroid cancer, although the deaths seemed unrelated to thyroid cancer.243 Longer follow-up suggests that OS is not decreased or increased in these patients.244 However, a 2011 study reported that the incidence of secondary malignancies, such as leukemia and salivary gland malignancies, has increased in patients with low-risk thyroid cancer (ie, T1N0) who received RAI.245 Debate continues about ablating the thyroid bed with iodine-131 after total thyroidectomy.173,240,246,247 In patients with papillary carcinoma who were at low risk for recurrence, thyroid remnant ablation did not decrease recurrence rates.212,237,248 A long-term study (n = 1298) found that OS is not improved in patients who receive RAI ablation.249 Reasons favoring remnant ablation include: 1) simplified patient follow-up, because elimination of thyroid bed uptake prevents misinterpretation of it as disease; 2) elimination of normal tissue as a source of Tg production, which facilitates identification of patients who are free of disease and may simplify their care while promoting early identification of those with residual cancer; and 3) elimination of normal tissue, which may eliminate the nidus for continued confounding anti-Tg antibody production. Conversely, others argue that most recurrences can be easily detected with neck ultrasound and that serum Tg levels are often quite low after a total thyroidectomy. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 82. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-16 Therefore, in patients at low and intermediate risk, the clinical benefit of routine remnant ablation as a requirement for optimal follow-up remains uncertain. Thyroid hormone withdrawal may be recommended to increase uptake from RAI treatment.250 Duration of time off thyroid hormone depends on the extent of thyroidectomy and approach to hormone replacement in the initial postoperative setting. Two retrospective studies showed that patients with distantly metastatic RAI-avid differentiated thyroid cancer who received recombinant human TSH in preparation for RAI treatment did not differ significantly in treatment response or survival, compared to patients who received RAI treatment after thyroid hormone withdrawal.251,252 However, thyroid hormone withdrawal continues to be preferred by the NCCN Panel for preparation of RAI treatment compared to thyrotropin alfa, due to an increased likelihood of augmentation of the delivered radiation dose. Guidance for preparing the patient and managing iodine-131 administration can be found in the Principles of Radiation and Radioactive Iodine Therapy: Iodine-131 Administration in the NCCN Guidelines for Thyroid Carcinoma. Data suggest that lower doses of RAI are as effective as higher doses—30 versus 100 mCi—for ablation in patients with low-risk thyroid cancer (eg, T1b/T2 [1–4 cm], clinical N0 disease).35,36,253 The NCCN Guidelines reflect a more cautious approach to using RAI ablation based on these randomized trials.254 If RAI ablation is used, the NCCN Guidelines recommend (category 1) 30 mCi of iodine-131 for RAI ablation in patients at low risk based on these randomized trials. This same ablation dose—30 mCi—may be considered (category 2B) in patients at slightly higher risk.255 RAI ablation is not recommended in patients at very low risk. RAI therapy for thyroid cancer carries the risk of possible adverse effects including salivary gland dysfunction, lacrimal gland dysfunction, transient gonadal dysfunction, and secondary primary malignancies.256 The possible benefits of RAI should be weighed with the risk of adverse effects as part of treatment decision-making.254 Adverse effects may be minimized by using lower doses of RAI.35 Historically, the three methods of determining iodine-131 therapy activities (doses) have included: empiric fixed doses, quantitative dosimetry, and upper-bound limits that are set by blood dosimetry.3,229,257,258 Most patients at NCCN Member Institutions receive postoperative RAI based on empiric fixed dosing; a few centers use a combination of blood dosimetry and quantitative lesional dosimetry. In the past, hospitalization was required to administer therapeutic doses of iodine-131 greater than 30 mCi (1110 MBq). However, hospitalization is no longer necessary in most states, because a change in federal regulations permits the use of much larger iodine-131 doses in patients who are ambulatory.257 However, iodine-131 therapy with high doses (200 mCi) is best done in medical centers with experience using high doses. Dosimetry can be used to determine the maximal safe dose for treatment of unresectable, large-volume, iodine- concentrating, residual, or recurrent disease. Administration of a fixed dose of iodine-131 is the most widely used and simplest method. Most clinics use this method regardless of the percentage uptake of iodine-131 in the remnant or metastatic lesion. Patients with uptake in tumor are routinely treated with large, fixed amounts of iodine-131. Lymph node metastases may be treated with about 100 to 175 mCi (3700–6475 MBq) of iodine-131. Cancer growing through the thyroid capsule (and incompletely resected) is treated with 150 to 200 mCi (5550–7400 MBq). Patients with distant metastases are usually treated with 100 to 200 mCi (3700–7400 MBq) of iodine-131, which typically will not induce radiation sickness or produce serious damage to other structures but may exceed generally accepted safety limits to the blood in the elderly and in those with impaired kidney function.259,260 Diffuse pulmonary metastases that concentrate 50% or Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 83. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-17 more of the diagnostic dose of iodine-131 (which is very uncommon) are treated with 150 mCi of iodine-131 (5550 MBq) or less to avoid lung injury, which may occur when more than 80 mCi remains in the whole body 48 hours after treatment. Guidance relating to pediatric patients, women who are breastfeeding or desiring pregnancy, or patients with end-stage renal disease on hemodialysis can be found in the Principles of Radiation and Radioactive Iodine Therapy: Iodine-131 Administration in the NCCN Guidelines for Thyroid Carcinoma. Post-Treatment Iodine-131 Imaging When iodine-131 therapy is given, whole body iodine-131 imaging should be performed several days later to document iodine-131 uptake by the tumor. Post-treatment whole body iodine-131 imaging should be done, primarily because up to 25% of images show lesions that may be clinically important, which were not detected by the diagnostic imaging.257 In a study of pre-treatment and post-treatment imaging, the two differed in 27% of the treatment cycles, but only 10% of the post-treatment imaging showed clinically significant new foci of metastatic disease.261 Post-treatment imaging was most likely to reveal clinically important new information in patients younger than 45 years who had received iodine-131 therapy in the past. Conversely, in older patients and patients who had not previously received iodine-131 therapy, post-treatment imaging rarely yielded new information that altered the patient’s prognosis.261 PET scan is indicated for patients with a negative whole body scan who have suspected structural disease based on other imaging methods and/or elevated Tg to a degree that would indicate distant metastasis.262 Assessment and Management After Initial Treatment Serum Tg determinations, neck ultrasound, and whole body iodine-131 imaging detect recurrent or residual disease in most patients who have undergone total thyroid ablation.263 In contrast, neither serum Tg nor whole body iodine-131 imaging is specific for thyroid carcinoma in patients who have not undergone thyroidectomy and remnant ablation. When initial ablative therapy has been completed, serum Tg should be measured periodically. Serum Tg can be measured while the patient is taking thyroxine, but older studies showed that the test was more sensitive when thyroxine had been stopped or when recombinant human TSH (rhTSH) was given to increase the serum TSH.264,265 With improved assay sensitivity, Tg stimulated by thyrotropin alfa is no longer more sensitive, and basal Tg on thyroxine can be monitored with accuracy and sensitivity.266,267 Using current Tg assays, patients with measurable serum Tg levels during TSH suppression and those with stimulated Tg levels greater than 2 ng/mL are likely to have residual/recurrent disease that may be localized in almost 50% promptly and in an additional 30% over the next 3 to 5 years.268 About 6% of patients with detectable serum Tg levels (which are 2 ng/mL after stimulation) will have recurrences over the next 3 to 5 years, whereas only about 2% of patients with completely undetectable serum Tg after stimulation will have recurrences over the next 3 to 5 years. The long-term clinical significance is uncertain for disease only detected by minimally elevated Tg levels after stimulation. Recombinant Human TSH During follow-up, periodic withdrawal of thyroid hormone therapy has traditionally been used to increase the serum TSH concentrations sufficiently to stimulate thyroid tissue so that serum Tg measurements with (or without) iodine-131 imaging could be performed to detect residual thyroid tissue or carcinoma. However, patients dislike thyroid hormone withdrawal, because it causes symptomatic hypothyroidism. An alternative to thyroid hormone withdrawal is the administration of thyrotropin alfa intramuscularly, which stimulates thyroidal iodine-131 uptake and Tg release while the patient continues thyroid hormone suppressive therapy and avoids symptomatic hypothyroidism.269 Administration of thyrotropin Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 84. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-18 alfa is well tolerated; nausea (10.5%) and transient mild headache (7.3%) are its main adverse effects.265 It is associated with significantly fewer symptoms and dysphoric mood states than hypothyroidism induced by thyroid hormone withdrawal.269 An international study was performed to assess the effects of two rhTSH dosing schedules on whole body iodine-131 imaging and serum Tg levels when compared with imaging and Tg levels obtained after thyroid hormone withdrawal.265 Data showed that the combination of rhTSH– stimulated whole body imaging and serum Tg measurements detected 100% of metastatic carcinoma.265 In this study, 0.9 mg of rhTSH was given intramuscularly every day for 2 days, followed by a minimum of 4 mCi of iodine-131 on the third day. Whole body imaging and Tg measurements were performed on the fifth day. Whole body iodine-131 images were acquired after 30 minutes of imaging or after obtaining 140,000 counts, whichever came first. A serum Tg of 2.0 ng/mL or higher, obtained 72 hours after the last rhTSH injection, indicates that thyroid tissue or thyroid carcinoma is present, regardless of the whole body imaging findings.265,270 Measuring Serum Tg and Anti-Tg Antibodies Serum Tg measurement is the best means of detecting thyroid tissue, including carcinoma. Tg can be measured when TSH has been stimulated—either by thyroid hormone withdrawal or by thyrotropin alfa— because in this setting, serum Tg has a lower false-negative rate than whole body iodine-131 imaging.264,265,268,271 Serum Tg levels vary in response to the increase in serum TSH after thyroid hormone withdrawal or TSH stimulation. Serum Tg generally does not increase as much after thyrotropin alfa as after withdrawal of thyroid hormone. The conditions for TSH–stimulated, whole body iodine-131 imaging stipulate using 4-mCi iodine-131 doses (based on the trial)265 and an imaging time of 30 minutes or until 140,000 counts are obtained. Tg measurements may also be obtained without stimulating TSH using ultrasensitive assays (ie, second- generation Tg immunometric assays [TgIMAs]).267,272 Evaluation of serum Tg and anti-Tg antibody levels is helpful for the purpose of obtaining a postoperative baseline. Functional sensitivity less than or equal to 0.1 ng/mL for Tg and 0.9 ng/mL for TgAb are reported for newer generation assays, compared to 1.0 ng/mL for Tg and 20 ng/mL for TgAb for older generation assays.266,267 With the availability of next-generation assays, it is now widely accepted that stimulated Tg is no longer necessary. Anti-Tg antibodies should be measured in the same serum sample taken for Tg assay, because these antibodies (which are found in ≤25% of patients with thyroid carcinoma) invalidate serum Tg measurements in most assays.272-274 These antibodies typically falsely lower the Tg value in immunochemiluminometric assays (ICMAs) and immunoradiometric assays (IRMAs), while raising the value in older radioimmunoassays. Although the clinical importance of anti-Tg antibodies is unclear, their persistence for more than 1 year after thyroidectomy and RAI ablation probably indicates the presence of residual thyroid tissue and possibly an increased risk of recurrence.274 In one study, 49% of patients had a recurrence if they had undetectable serum Tg and serum anti-Tg antibody levels of 100 units/mL or more when compared with only 3% of patients with undetectable serum Tg and serum anti-Tg antibodies of less than 100 units/mL.275 In patients with coexistent autoimmune thyroid disease at the time of surgery, anti-Tg antibodies may persist for far longer. In a study of 116 patients with anti-Tg antibodies before thyroidectomy, antibodies remained detectable for up to 20 years in some patients without detectable thyroid tissue, and the median time to disappearance of antibodies was 3 years.276 Patients with persistently undetectable serum Tg and anti-Tg antibody levels have longer DFS when compared with patients who have detectable levels.277 Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 85. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-19 Treating Patients with Positive Tg and Negative Imaging Post-treatment iodine-131 imaging may indicate the location of metastases when the serum Tg level is increased, but a tumor [or metastases] cannot be found by physical examination or other localizing techniques such as diagnostic iodine-131 imaging, neck ultrasonography, CT, MRI, or PET. Pulmonary metastases may be found only after administering therapeutic doses of iodine-131 and obtaining whole body imaging within a few days of treatment.278 In a study of 283 patients treated with 100 mCi (3700 MBq) of iodine-131, 6.4% had lung and bone metastases detected after treatment that had been suspected based on high serum Tg concentrations alone but that had not been detected after 2-mCi (74 MBq) diagnostic imaging.279 Unfortunately, most patients who are diagnostic imaging–negative and Tg-positive are not rendered disease free by iodine-131 therapy; however, the tumor burden may be diminished.280 Thus, most patients with residual or recurrent disease confined to the neck undergo reoperation rather than RAI therapy in the hopes of a cure. RAI therapy is more commonly considered for those with distant metastases or inoperable local disease. Patients not benefiting from this therapy can be considered for clinical trials, especially those patients with progressive metastatic disease. When a large tumor is not visible on diagnostic whole body imaging, its ability to concentrate iodine-131 is very low; thus, the tumor will not respond to iodine-131 therapy. Thyroid Hormone Suppression of TSH The use of postoperative levothyroxine to decrease TSH levels is considered optimal in treatment of patients with papillary, follicular, or Hürthle cell carcinoma, because TSH is a trophic hormone that can stimulate the growth of cells derived from thyroid follicular epithelium.246,281- 283 However, the optimal serum levels of TSH have not been defined because of a lack of specific data; therefore, the NCCN Panel recommends tailoring the degree of TSH suppression to the risk of recurrence and death from thyroid cancer for each individual patient. For patients with known residual carcinoma or those at high risk for recurrence, the recommended TSH level is below 0.1 mU/L. For patients at low risk and for those patients with an excellent response to initial therapy who are in remission, the recommended TSH level is either slightly below or slightly above the lower limit of the reference range (0.5– 2 mU/L). The risks and benefits of TSH-suppressive therapy must be balanced for each individual patient because of the potential toxicities associated with TSH-suppressive doses of levothyroxine, including cardiac tachyarrhythmias (especially in the elderly), bone demineralization (particularly in post-menopausal women), and frank symptoms of thyrotoxicosis.3,284,285 An adequate daily intake of calcium (1200 mg/day) and vitamin D (1000 units/day) is recommended for patients whose TSH levels are chronically suppressed. However, reports do not suggest that bone mineral density is altered in patients receiving levothyroxine.286,287 Decreased recurrence and cancer-specific mortality rates for differentiated thyroid carcinoma have been reported for patients treated with thyroid hormone suppressive therapy.12,240,243,283,288-290 The average dosage needed to attain serum TSH levels in the euthyroid range is higher in patients who have been treated for thyroid carcinoma (2.11 mcg/kg per day) than in those patients with spontaneously occurring primary hypothyroidism (1.62 mcg/kg per day).290 Even higher doses are required to suppress serum TSH in patients who have been treated for thyroid carcinoma. The optimal TSH level to be achieved is uncertain in patients who have been treated for thyroid carcinoma. Superior outcomes were associated with aggressive thyroid hormone suppression therapy in patients at high risk but were achieved with modest suppression in patients with stage II disease.243 Excessive TSH suppression (into the undetectable, thyrotoxic range) is not required to prevent disease Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 86. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-20 progression in all patients who have been treated for differentiated thyroid carcinoma. Adjuvant External-Beam RT No prospective controlled trials have been completed using adjuvant external-beam radiation therapy (EBRT).291-293 One retrospective study reported a benefit of adjuvant EBRT after RAI in patients older than 40 years with invasive papillary carcinoma (T4) and lymph node involvement (N1).294 Local recurrence and locoregional and distant failure were significantly decreased. A second study reported increased cause-specific survival and local relapse-free rate in select patients treated with adjuvant EBRT (in addition to total thyroidectomy and TSH-suppressive therapy with thyroid hormone) for papillary carcinoma with microscopic residuum. Not all patients received RAI therapy.110 Benefit was not shown in patients with follicular thyroid carcinoma or other subgroups of papillary carcinoma. Similarly, patients with microscopic residual papillary carcinoma postoperatively are more commonly rendered disease free after receiving EBRT (90%) than those who do not receive it (26%).295 A third study showed that postoperative EBRT was associated with reduced risk of locoregional failure in patients with thyroid cancer that is pT3-4, pN+, or with R1 or R2 resection (N = 254; HR, 0.17; 95% CI, 0.10–0.29; P .001), although no impact was observed on OS (P = .600).296 Another retrospective study suggested that postoperative EBRT may improve survival in patients with macroscopic extrathyroidal extension following surgery.297 Finally, another study found that recurrences did not occur in patients at high risk who received EBRT, but recurrences did occur in those who did not receive EBRT. However, the study was not powered to detect a statistical significance.298 Other data from single institutions also show that adjuvant EBRT yields long-term control of locoregional disease.299-301 Studies suggest that intensity-modulated RT (IMRT) is safe, effective, and less morbid in patients with thyroid cancer.296,299,302 There is little evidence regarding appropriate treatment volumes for use of RT for thyroid carcinoma, but 60 to 66 Gy for the postoperative setting (up to 70 Gy for incomplete resection) is supported by a 2011 review of studies in this area.293 Additional guidance on EBRT dose and fractionation in the adjuvant setting can be found in the Principles of Radiation and Radioactive Iodine Therapy: External Beam Radiation Therapy in the NCCN Guidelines for Thyroid Carcinoma. External-Beam RT and Surgical Excision of Metastases Surgical excision, EBRT, stereotactic body RT (SBRT), or other local therapies can be considered for symptomatic isolated skeletal metastases or those that are asymptomatic in weight-bearing sites.303,304 Brain metastases pose a special problem, because iodine-131 therapy may induce cerebral edema. Neurosurgical resection can be considered for brain metastases. For solitary brain lesions, either neurosurgical resection or stereotactic radiosurgery (SRS) is preferred over whole brain radiation.305,306 Once brain metastases are diagnosed, disease-specific mortality is very high (67%), with a reported median survival of 12.4 months in one retrospective study. Survival was significantly improved by surgical resection of one or more tumor foci.307 Most recurrent tumors respond well to surgery; iodine-131 therapy; or EBRT, SBRT, or IMRT.3,308 Local therapies such as ethanol ablation, cryoablation, or radiofrequency ablation (RFA) may be considered for select patients with limited burden nodal disease.3 Systemic Therapy Systemic therapy can be considered for tumors that are not surgically resectable; are not responsive to iodine-131; are not amenable to EBRT treatment, SBRT, IMRT, or other local therapies; and have clinically significant structural disease progression during the last 6 to 12 months. Enrollment in neoadjuvant clinical trials should be encouraged. Overall, traditional cytotoxic systemic chemotherapy, such as doxorubicin, has minimal efficacy in patients with metastatic differentiated thyroid Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 87. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-21 disease.309 Novel treatments for patients with metastatic differentiated thyroid carcinoma have been evaluated.310-317 Agents include multitargeted kinase inhibitors, such as lenvatinib,310,313,318-325 sorafenib,326-333 sunitinib,331,334,335 axitinib,336-338 everolimus,339,340 vandetanib,341 cabozantinib,311,342 and pazopanib343 ; BRAF V600E mutant inhibitors, such as vemurafenib or dabrafenib344-347 ; tropomyosin receptor kinase (TRK) inhibitors, such as larotrectinib or entrectinib348,349 ; RET inhibitors such as selpercatinib or pralsetinib350,351 ; and anti-PD-1 antibodies such as pembrolizumab.352 Data suggest that anaplastic lymphoma kinase (ALK) inhibitors may be effective in patients with papillary carcinoma who have ALK gene fusion.353-356 Clinical trials suggest that kinase inhibitors have a clinical benefit (partial response rates plus stable disease) in 50% to 60% of subjects, usually for about 12 to 24 months.313,321,331,343,357-359 Lenvatinib is the preferred systemic therapy option for the treatment of patients with RAI-refractory differentiated thyroid cancer (see Papillary Thyroid Carcinoma in this Discussion and the NCCN Guidelines for Papillary [Thyroid] Carcinoma). Vandetanib and cabozantinib, oral kinase inhibitors, are preferred systemic therapy options for the treatment of medullary carcinoma in patients with unresectable locally advanced or metastatic disease, and RET inhibitors (selpercatinib and pralsetinib) are preferred options for RET mutation-positive disease (see Medullary Thyroid Carcinoma in this Discussion and the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Cabozantinib is also an option for RAI-refractory differentiated thyroid carcinoma that has progressed on VEGFR-targeted therapies such as lenvatinib and sorafenib.360 Severe or fatal side effects from kinase inhibitors include bleeding, hypertension, stroke, and liver toxicity; however, most side effects can be managed and are reversible with discontinuation of the drug.320,321,361-366 Dose modifications of kinase inhibitors may be required. Pazopanib has been reported to cause reversible hypopigmentation.367 Papillary Thyroid Carcinoma Surgical Therapy Imaging is performed before surgery to ascertain the extent of disease and to aid in the surgical decision-making process. A cervical ultrasound, including the thyroid and the central and lateral compartments, is the recommended principal imaging modality.368 In one report, cervical ultrasound performed before primary surgery for newly diagnosed thyroid cancer identified metastatic sites not appreciated on physical examination in 20% of patients, and surgical strategy was altered in 39% of patients.369 Surgeon-performed preoperative ultrasound identified nonpalpable metastatic lymph nodes in 24% of patients.370 In more than 700 patients with PTC, preoperative ultrasound detected nonpalpable nodal metastases in 33% of subjects.371 Preoperative ultrasound findings altered the operation in more than 40% of cases. In another report,372 operative management was altered in 23% of the total group due to findings on the preoperative ultrasound. These studies indicate that preoperative ultrasound has a high sensitivity for nodal disease and will detect nonpalpable nodal metastases in 20% to 33% of patients, and ultrasound should alter the index operation in a similar percentage of patients. In most cases, lesions suspicious for locoregional recurrence, which are amenable to needle biopsy, should be interrogated with FNA biopsy before surgery. Tg washout assay is a useful adjunct to FNA biopsy in these cases, particularly if cytology is negative. Cross-sectional imaging (CT or MRI) should be performed for locally advanced disease (eg, if the thyroid lesion is fixed, bulky, or substernal) or for vocal cord paresis. Iodinated contrast is required for optimal cervical imaging with CT, although iodinated contrast will delay treatment with RAI; delaying RAI treatment is not harmful. Assessment of vocal cord mobility is recommended for patients with abnormal voice, a surgical history involving the recurrent laryngeal or vagus nerves, invasive disease, or bulky disease of the central neck. Evaluation is essential in patients with voice changes. Vocal cord mobility Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 88. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-22 may be evaluated by ultrasound, mirror indirect laryngoscopy, or fiber- optic laryngoscopy.373 The NCCN Panel agreed on the characteristics of patients at higher risk who require total thyroidectomy as the primary treatment (see Preoperative or Intraoperative Decision-Making Criteria in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).3,374,375 A total thyroidectomy is recommended for patients with any one of the following factors, including: known distant metastases, extrathyroidal extension, tumor larger than 4 cm in diameter, lateral cervical lymph node metastases or gross central neck lymph node metastases, or poorly differentiated histology. Total thyroidectomy may be considered for patients with bilateral nodularity or a prior exposure to radiation (category 2B for radiation exposure). Clinically positive and/or biopsy-proven nodal metastases should be treated with a formal compartmental resection. In the central neck, this is achieved through a unilateral or bilateral level VI dissection. In the lateral compartment, a formal modified radical neck dissection including levels II, III, IV, and Vb should be performed.376 Extending the dissection field into levels I or Va may be necessary when these levels are clinically involved. Based on the results of two randomized controlled trials, the panel does not recommend prophylactic central neck dissection if the cervical lymph nodes are clinically negative. Two trials of randomized patients with cN0 PTC to receive either total thyroidectomy alone or total thyroidectomy plus central neck dissection showed no difference in outcomes between the two groups.377,378 Central neck dissection will be required ipsilateral to a modified radical neck dissection done for clinically involved lateral neck lymph nodes in most cases. Selective dissection of individual nodal metastases (ie, cherry picking) is not considered adequate surgery for nodal disease in a previously undissected field. The NCCN Panel did not uniformly agree about the preferred primary surgery for patients with PTC who are assumed to be at lower risk of cancer-specific mortality. As previously mentioned, the extent of thyroid resection—ipsilateral lobectomy versus total thyroidectomy—is very controversial for lower-risk PTC, and lobectomy is preferred for these patients, while total thyroidectomy is a category 2B option (see Ipsilateral Lobectomy Versus Total Thyroidectomy in this Discussion). Lobectomy plus isthmusectomy is recommended for patients who cannot (or refuse to) take thyroid hormone replacement therapy for the remainder of their lives.222 Note that some patients prefer to have total thyroidectomy to avoid having a second surgery (ie, completion thyroidectomy). Other patients prefer to have a lobectomy in an attempt to avoid thyroid hormone replacement therapy. Most guidelines (eg, NCCN, ATA3 ) do not recommend active surveillance for patients with PTC. However, for PTC 1 cm or smaller and no concerning lymph node involvement or risk features (eg, posterior location, abutting the trachea or apparent invasion), surgery may not be warranted, and active surveillance with ultrasound may be sufficient.379-382 A study of more than 5000 patients found that survival of patients after partial thyroidectomy was similar to the survival after total thyroidectomy for patients at low and high risk.383 An observational study (SEER database) in more than 35,000 patients with PTC limited to the thyroid gland suggests that survival is similar whether (or not) patients are treated in the first year after diagnosis and whether they undergo lobectomy or total thyroidectomy.384 Another study of 2784 patients with differentiated thyroid carcinoma (86% with PTC) found that total thyroidectomy was associated with increased survival in patients at high risk.243 A study in 52,173 patients found that total thyroidectomy reduces recurrence rates and improves survival in patients with PTC of 1 cm or larger when compared with lobectomy.385 For patients at lower risk who undergo lobectomy plus isthmusectomy, completion of thyroidectomy is recommended for any one of the following Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 89. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-23 risk factors: large tumor (4 cm), gross positive resection margins, gross extrathyroidal extension, confirmed contralateral disease, vascular invasion, poorly differentiated disease, or confirmed nodal metastases. While a retrospective study using the National Cancer Database has shown that a sizable percentage of patients with differentiated thyroid cancer receive RAI therapy following lobectomy,386 the panel does not support this practice due to a lack of data showing benefit. Therefore, RAI is not recommended following lobectomy for differentiated thyroid cancer. PTC with lymphatic invasion or macroscopic multifocal disease (1 cm) may warrant a completion thyroidectomy (see Primary Treatment in the NCCN Guidelines for Papillary [Thyroid] Carcinoma); disease monitoring (category 2B) is another option for these patients. Measurement of Tg and anti-Tg antibodies may be useful for obtaining a postoperative baseline, but data to interpret these antibodies in the setting of an intact thyroid lobe are lacking.387 Levothyroxine therapy can be considered for these patients to maintain low or normal TSH levels (see Principles of TSH Suppression in the NCCN Guidelines for Thyroid Carcinoma). Disease monitoring is sufficient for tumors resected with lobectomy with all of the following: negative resection margins, no contralateral lesion, no suspicious lymph node(s), and small (≤4 cm) PTCs. Levothyroxine therapy to reduce serum TSH to low or low-normal concentrations can be considered for these patients (see Principles of TSH Suppression in the NCCN Guidelines for Thyroid Carcinoma). Radioactive Iodine Therapy Postoperative RAI administration is recommended when a number of clinical factors predict a significant risk of recurrence, distant metastases, or disease-specific mortality. Clinicopathologic factors can be used to guide decisions about whether to use initial postoperative RAI (see Clinicopathologic Factors in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). Algorithms can assist in decision-making about use of RAI in different settings: 1) RAI is not typically indicated for patients classified as having a low risk of recurrence/disease-specific mortality; 2) RAI is not recommended after lobectomy; 3) RAI may be considered for patients without gross residual disease, but data are conflicting regarding the benefit of RAI in this setting; and 4) RAI is often used for patients with known or suspected distant metastatic disease at presentation. However, some patients may have metastatic disease that may not be amenable to RAI therapy, which is also known as iodine-refractory disease (see Treatment of Metastatic Disease Not Amenable to RAI Therapy in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). Even in the absence of thyroid bed uptake, postoperative RAI treatment may be considered. RAI is also often used to reduce the risk of recurrent thyroid cancer in patients deemed higher-risk based on surgical pathology, even if there is no evidence of structural or biochemical disease present initially in the postoperative period (see Recurrent Disease in this Discussion). All patients should be examined, and cross-sectional imaging (CT or MRI of neck with contrast) should be used to evaluate gross residual disease. Palpable neck disease should be surgically resected before any RAI treatment. A negative pregnancy test is required before the administration of RAI in women of childbearing potential. The administered activity of RAI therapy should be adjusted for pediatric patients.388 Dose should also be modified if higher than expected uptake, such as in the event of residual thyroid uptake or distant metastasis. For patients with unresectable gross residual disease in the neck (RAI uptake absent) that is refractory to RAI, EBRT or IMRT can be considered if disease is threatening vital structures, is viscerally invasive, or is rapidly progressing (see Postsurgical Evaluation in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).3,299,300,389-391 Enrollment in a neoadjuvant clinical trial should be considered. Patients with bulky, locoregional, viscerally invasive disease or rapid progression should be referred to a Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 90. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-24 high-volume multidisciplinary institution, including referral to a radiation oncologist. Patients with unresectable gross residual disease who received upfront EBRT or IMRT and with absent RAI should be monitored, or systemic therapy treatment may be considered. Surveillance and Maintenance The recommendations for surveillance and maintenance are described in the algorithm (see Disease Monitoring in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). About 85% of patients are considered to be low risk after surgery for papillary thyroid cancer.246 In patients treated with lobectomy, disease monitoring following surgery includes physical examination, TSH assessment, and periodic neck ultrasound. If abnormal contralateral nodule or lymph nodes are found, then biopsy should be carried out. In patients who have had total (or near total) thyroidectomy and thyroid remnant ablation, the ATA Guidelines define the absence of persistent tumor (also known as no evidence of disease [NED]) as: 1) absence of clinical evidence of tumor; 2) absence of imaging evidence of tumor; and 3) undetectable Tg levels (during either TSH suppression or TSH stimulation) and absence of anti-Tg antibodies.3 Patients treated with total thyroidectomy should be followed with physical examination and measurement of TSH, Tg, and Tg ab. RAI imaging (TSH-stimulated [during either TSH suppression or TSH stimulation]) can be considered in patients at high risk for persistent or recurrent disease, distant metastases, or disease-specific mortality; patients with previous RAI-avid metastases; or patients with abnormal Tg levels, stable or increasing Tg ab, or abnormal ultrasound results. A tumor is considered iodine-responsive if follow-up iodine-123 or low-dose iodine-131 whole body diagnostic imaging done 6 to 12 months after iodine-131 treatment is negative or shows decreasing uptake compared to pretreatment scans.3 Favorable response to iodine-131 treatment is also assessed through change in volume of known iodine-concentrated lesions by CT or MRI, as well as by decreasing unstimulated or stimulated Tg levels.3 A subgroup of patients at low risk (eg, micropapillary carcinomas entirely confined to the thyroid gland) may only require periodic neck ultrasound follow-up (without stimulated Tg or follow-up whole body imaging) as long as their basal Tg remains low (see Disease Monitoring in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). Otherwise, long-term ultrasound follow-up is not required. Note that Tg should be measured using the same laboratory and the same assay, because Tg levels vary widely between laboratories.3 Patients with clinically significant residual disease can typically be identified by the trend in Tg levels over time.3 Non-RAI imaging—such as ultrasound of the central and lateral neck compartments, neck CT, chest CT, or FDG-PET/CT—may be considered if RAI imaging is negative and stimulated Tg is greater than 2 to 5 ng/mL. High-risk factors include incomplete tumor resection, macroscopic tumor invasion, and distant metastases in patients at high risk for persistent or recurrent disease, distant metastases, or disease-specific mortality (see Consideration for Initial Postoperative RAI Therapy in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).3 Recurrent Disease The NCCN Panel agrees that surgery is the preferred therapy for locoregional recurrent disease if the tumor is resectable (see Recurrent Disease in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). Cervical ultrasound, including the central and lateral compartments, is the principal imaging modality when locoregional recurrence is suspected.3 Cross-sectional imaging with CT or MRI may also be valuable for evaluation and surgical planning, especially when reliable high-resolution diagnostic ultrasound is unavailable and/or there is suspicion of invasion into the aerodigestive tract. In most cases, lesions suspicious for Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 91. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-25 locoregional recurrence, which are amenable to needle biopsy, should be interrogated with FNA biopsy before surgery. Tg washout assay may be a useful adjunct to FNA biopsy in these cases, particularly if cytology is negative. Preoperative iodine whole body scan can be used to guide subsequent use of RAI or other follow-up approach. Clinically significant nodal recurrence in a previously undissected nodal basin should be treated with a formal compartmental resection.3 In the central neck, this is usually achieved through a unilateral level VI dissection and, occasionally, a level VII dissection. In the lateral compartment, a formal modified radical neck dissection—including levels II, III, IV, and Vb—should be performed. Extending the dissection field into levels I or Va may be necessary when these levels are clinically involved. Selective dissection of individual nodal metastases (cherry picking) is not considered adequate surgery for nodal disease in a previously undissected field, and is not recommended in the NCCN Guidelines for Thyroid Carcinoma. Clinically significant nodal recurrence detected in a previously dissected nodal basin may be treated with a more focused dissection of the region containing the metastatic disease. For example, a level II recurrence detected in a patient who underwent a modified radical neck dissection as part of the primary treatment may only require selective dissection of level II. Likewise, a central neck recurrence detected in a patient who underwent a central neck dissection as part of the primary treatment may only require a focused resection of the region of recurrence. For unresectable locoregional recurrence, RAI treatment and EBRT or IMRT are recommended if the iodine-131 imaging is positive.392 Local therapies, such as ethanol ablation or RFA, are also an option if available.393 EBRT or IMRT alone is another option in the absence of iodine-131 uptake for select patients not responsive to other therapies.300,394 EBRT improves local control in patients with gross residual non-RAI–avid disease following surgery.293 When recurrent disease is suspected based on progressively rising Tg values (basal or stimulated) and negative imaging studies (including PET scans), RAI therapy can be considered using an empirically determined dose of greater than or equal to 100 mCi of iodine-131 (see Recurrent Disease in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). The NCCN Panel had a major disagreement (category 3) about recommending post-treatment iodine-131 imaging in this setting, because some do not feel that these patients should have imaging. No study has shown a decrease in morbidity or mortality in patients treated with iodine-131 on the basis of increased Tg measurements alone. In a long-term follow-up study, no survival advantage was associated with empiric high-dose RAI in patients with negative imaging.395 Further, potential long-term side effects (ie, xerostomia, nasolacrimal duct stenosis, bone marrow and gonadal compromise, the risk of hematologic and other malignancies) may negate any benefit.396,397 Active surveillance may be considered for patients with low-volume disease that is stable and distant from critical structures. Metastatic Disease RAI therapy may be used to treat metastatic disease that is iodine-avid, or local therapies such as ethanol ablation, cryoablation, or RFA may be used for these patients, if available. For metastatic disease not amenable to RAI therapy, several therapeutic approaches are recommended, depending on the site and number of tumor foci (see Treatment of Metastatic Disease Not Amenable to RAI Therapy in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).3,398 Patients should continue to receive levothyroxine to suppress TSH levels. If not already done, then genomic testing should be done to identify potentially actionable mutations (eg, ALK, NTRK, and RET gene fusions; DNA mismatch repair deficiency [dMMR]; microsatellite instability [MSI]; tumor mutational burden [TMB]). Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 92. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-26 For skeletal metastases, consider surgical palliation for symptomatic or asymptomatic tumors in weight-bearing extremities; other therapeutic options are EBRT, SBRT, or other local therapies.303,304,399-401 Intravenous bisphosphonate (eg, pamidronate or zoledronic acid) or denosumab therapy may be considered for bone metastases; data show that these agents prevent skeletal-related events.402-404 Embolization (or other interventional procedures) of metastases can also be considered either prior to resection or as an alternative to resection.399,405 RAI is not likely to be curative, but improved survival has been observed in these patients.184,406 For solitary or limited CNS lesions, either neurosurgical resection or SRS is preferred (see the NCCN Guidelines for Central Nervous System Cancers).305,306 For multiple CNS lesions, EBRT can be considered,293 as well as surgical resection for select cases such as for acute decompression (see Treatment of Metastatic Disease Not Amenable to RAI Therapy in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). For multiple or extensive CNS lesions, radiotherapy (SRS or whole brain RT) is recommended, with resection in select cases. If whole brain RT is used, then 30 Gy in 10 daily fractions, or 45 Gy in 1.8 Gy daily fractions if good performance status, are acceptable dosing schedules.407 For clinically progressive or symptomatic disease, systemic therapy should be considered. Recommended systemic therapy options include: 1) lenvatinib (preferred) or sorafenib;320,326 2) clinical trials; 3) other small- molecule kinase inhibitors if a clinical trial is not available; or 4) resection of distant metastases and/or EBRT or IMRT.408,409 Lenvatinib and sorafenib are category 1 options in this setting based on phase 3 randomized trials.320,326 The NCCN Panel feels that lenvatinib is the preferred agent in this setting based on a response rate of 65% for lenvatinib when compared with 12% for sorafenib, although these agents have not been directly compared.318,320,326 The decision to use lenvatinib or sorafenib should be individualized for each patient based on likelihood of response and comorbidities. The efficacy of lenvatinib or sorafenib for patients with brain metastases has not been established; therefore, consultation with neurosurgeons and radiation oncologists is recommended. Kinase inhibitors have been used as second-line therapy for thyroid cancer.321,410 Lenvatinib was compared with placebo in patients with metastatic differentiated thyroid cancer that was refractory to RAI in a phase 3 randomized trial.320 Patients receiving lenvatinib had a progression-free survival (PFS) of 18.3 months compared with 3.6 months for those receiving placebo (HR, 0.21; 99% CI, 0.14–0.31; P .001). Six treatment- related deaths occurred in the lenvatinib group. A prespecified subset analysis of this trial found that the PFS benefit of lenvatinib compared to placebo was maintained in both older (65 years) and younger (≤65 years) patients. Furthermore, a longer median OS was observed in older patients treated with lenvatinib compared to placebo (HR, 0.27; 95% CI, 0.31–0.91; P = .20), although older patients also had higher rates of grade 3 and greater adverse effects from treatment. These results suggest that lenvatinib is an appropriate treatment option for patients of any age with RAI-refractory differentiated thyroid cancer.411 Another phase 3 randomized trial compared sorafenib with placebo in patients with RAI-refractory metastatic differentiated thyroid cancer.326 Patients receiving sorafenib had a PFS of 10.8 months compared with 5.8 months for those receiving placebo (HR, 0.59; 95% CI, 0.45–0.76; P .0001). One treatment-related death occurred in the sorafenib group. Hand-foot syndrome is common with sorafenib and may require dose adjustments. A phase 3 randomized trial compared cabozantinib to placebo in patients with RAI-refractory differentiated thyroid cancer that progressed during or after treatment with one or two vascular endothelial growth factor receptor Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 93. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-27 (VEGFR) TKIs (including lenvatinib and sorafenib).360 Analyses of the ITT population (n = 187) showed that the median PFS was not reached in patients receiving cabozantinib, compared with 1.9 months for those receiving placebo (HR, 0.22; 99% CI, 0.13–0.36; P .0001). Serious treatment-related adverse events occurred in 16% of patients in the cabozantinib arm, compared with 2% in the placebo arm, though no treatment-related deaths occurred. Cabozantinib is a category 1 option for patients with disease progression after lenvatinib and/or sorafenib. Other commercially available small-molecule kinase inhibitors may also be considered for progressive and/or symptomatic disease if a clinical trial is not available—including vemurafenib or dabrafenib (for BRAF-positive disease), larotrectinib or entrectinib (for NTRK gene fusion-positive disease), selpercatinib or pralsetinib (for RET fusion-positive disease), axitinib, everolimus, pazopanib, sunitinib, vandetanib, or cabozantinib— although some of these have not been approved by the FDA for differentiated thyroid cancer (see Principles of Kinase Inhibitor Therapy in Advanced Thyroid Carcinoma in the NCCN Guidelines for Thyroid Carcinoma). Note that kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease,320,326,362,412,413 and caution should be used in patients with untreated CNS metastases due to the associated bleeding risk.414 The anti-PD-1 antibody pembrolizumab is also an option for patients with TMB-high (TMB-H) (≥10 mutations/megabase [mut/Mb]) disease.352 Active surveillance is often appropriate for asymptomatic patients with indolent disease and no brain metastasis.321,362 Palliative care is recommended as indicated for patients with advanced and progressive disease (see the NCCN Guidelines for Palliative Care, available at www.NCCN.org). Follicular Thyroid Carcinoma The diagnosis and treatment of papillary and follicular thyroid carcinoma are similar; therefore, only the important differences in the management of follicular carcinoma are highlighted. The diagnosis of follicular thyroid carcinoma requires evidence of invasion through the capsule of the nodule or the presence of vascular invasion.48,415 Unlike PTC, FNA is not specific for follicular thyroid carcinoma and accounts for the main differences in management of the two tumor types.56,62,97,416 The FNA cytologic diagnosis of “[suspicious for] follicular neoplasm” will prove to be a benign follicular adenoma in 80% of cases. However, 20% of patients with follicular neoplasms on FNA are ultimately diagnosed with follicular thyroid carcinoma when the final pathology is assessed. Molecular diagnostic testing may be useful to determine the status of follicular lesions or lesions of indeterminate significance (including follicular neoplasms, AUS, or FLUS) as more or less likely to be malignant based on the genetic profile. Because most patients with follicular neoplasms on FNA actually have benign disease, total thyroidectomy is recommended only if radiographic evidence or interoperative findings of extrathyroidal extension or tumor larger than 4 cm in diameter are apparent at the time of surgery, or if the patient opts for total thyroidectomy to avoid a second procedure (ie, completion thyroidectomy) if cancer is found at pathologic review.415,417 Otherwise, lobectomy plus isthmusectomy is advised as the initial surgery. If invasive follicular thyroid carcinoma (widely invasive or encapsulated angioinvasive with four or more vessels) is found on the final histologic sections after lobectomy plus isthmusectomy, prompt completion of thyroidectomy is recommended (see Primary Treatment in the NCCN Guidelines for Follicular [Thyroid] Carcinoma). Completion thyroidectomy may also be recommended for tumors that, on final histologic sections after lobectomy plus isthmusectomy, are identified as minimally invasive follicular thyroid carcinomas or encapsulated angioinvasive with less than four vessels. Minimally invasive cancer is characterized as an encapsulated tumor with microscopic capsular invasion and without vascular invasion.3 It is preferred for minimally Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 94. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-28 invasive cancers, as well as NIFTP tumors, to simply be followed carefully, because minimally invasive follicular carcinomas and NIFTP usually have an excellent prognosis. Although deaths attributed to minimally invasive follicular carcinoma do occasionally occur, the panel feels that the benefit of completion thyroidectomy for small minimally invasive follicular cancers may not justify the additional morbidity. The other features of management and follow-up for follicular thyroid carcinoma are similar to those of PTC. Clinicopathologic factors can be used to guide decisions about whether to administer initial postoperative RAI (see Clinicopathologic Factors in the NCCN Guidelines for Follicular [Thyroid] Carcinoma). The NCCN Guidelines provide algorithms to assist in decision-making about use of RAI in different settings: 1) RAI is not typically indicated for patients classified as having a low risk of recurrence/disease-specific mortality; 2) RAI may be considered for patients without gross residual disease, but data are conflicting regarding the benefit of RAI in this setting; and 3) RAI is often used for patients with known or suspected distant metastatic disease (see Clinicopathologic Factors in the NCCN Guidelines for Follicular [Thyroid] Carcinoma). RAI ablation may be used to destroy residual thyroid tissue when RAI uptake is absent; alternatively, these patients may be followed without RAI ablation. Iodine-131 ablation and post-treatment imaging (with consideration of dosimetry for distant metastasis) are recommended for suspected or proven iodine-131–avid metastatic foci (see RAI Being Considered Based on Clinicopathologic Features in the NCCN Guidelines for Follicular [Thyroid] Carcinoma). In patients with known or suspected distantly metastatic disease, radioiodine diagnostic imaging (iodine-123 or iodine-131) with adequate TSH stimulation (thyroid withdrawal or thyrotropin alfa) before iodine-131 therapy is administered may be considered, but the problem of stunning should be considered (see section on Diagnostic Whole Body Imaging and Thyroid Stunning in this Discussion). For patients who have a central neck recurrence, preoperative vocal cord assessment should be considered (see Recurrent Disease in the NCCN Guidelines for Follicular [Thyroid] Carcinoma). Hürthle Cell Carcinoma This tumor (also known as oxyphilic cell carcinoma) is usually assumed to be a variant of follicular thyroid carcinoma,189,418 although the prognosis of Hürthle cell carcinoma is worse.164,415,417,419,420 The Hürthle cell variant of PTC is rare and seems to have a prognosis similar to follicular carcinoma.421 Historically, studies showed that molecular diagnostics did not perform well for Hürthle cell neoplasms.83,87,88 However, with the advent of newer genomic tests, the validity for Hürthle cell carcinoma is improving (see FNA Results in this Discussion, above).88,89 The management of Hürthle cell carcinoma is almost identical to follicular thyroid carcinoma, except that 1) locoregional nodal metastases may be more common, and therefore therapeutic lymph node dissections of the affected compartment may be needed for clinically apparent biopsy- proven disease; and 2) metastatic Hürthle cell tumors are less likely to concentrate iodine-131 (see Papillary Thyroid Carcinoma: Surgical Therapy in this Discussion).422 Postoperative EBRT or IMRT can be considered for: 1) unresectable primary Hürthle cell lesions that do not concentrate iodine-131 if disease is threatening vital structures; and 2) unresectable locoregional recurrence (see Postsurgical Evaluation and Recurrent Disease in the NCCN Guidelines for Hürthle Cell [Thyroid] Carcinoma), similar to the management for follicular thyroid carcinoma. Clinicopathologic factors can be used to guide decisions about whether to use initial postoperative RAI (see Clinicopathologic Factors in the NCCN Guidelines for Hürthle Cell [Thyroid] Carcinoma). The NCCN Guidelines provide algorithms to assist in decision-making about use of RAI in different settings: 1) RAI is not typically indicated for patients classified as Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 95. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-29 having a low risk of recurrence/disease-specific mortality; 2) RAI may be considered for patients without gross residual disease, but data are conflicting regarding the benefit of RAI in this setting; and 3) RAI is often used for patients with known or suspected distant metastatic disease (see Clinicopathologic Factors in the NCCN Guidelines for Hürthle cell [Thyroid] Carcinoma). RAI therapy has been reported to decrease the risk of locoregional recurrence and is recommended for unresectable disease with positive iodine-131 imaging. Iodine-131 therapy (100–150 mCi) may be considered after thyroidectomy for patients with rising or newly elevated Tg levels who have negative scans (including FDG-PET) (see Recurrent Disease in the NCCN Guidelines for Hürthle Cell [Thyroid] Carcinoma).164 Pretreatment radioiodine diagnostic imaging (iodine-123 or iodine-131) with adequate TSH stimulation (thyroid withdrawal or thyrotropin alfa) may be considered in patients with known or suspected distantly metastatic disease (see RAI Being Considered Based on Clinicopathologic Features in the NCCN Guidelines for Hürthle Cell [Thyroid] Carcinoma). Since Hürthle cell carcinoma tends to be non–iodine-avid, negative scans that were done without single-photon emission CT (SPECT) are likely to have missed distant structural disease. Therefore, if Tg is high and/or pathology is high- risk, then FDG-PET is indicated. Medullary Thyroid Carcinoma Medullary thyroid carcinoma (MTC) arises from the neuroendocrine parafollicular C cells of the thyroid.423-426 Sporadic MTC accounts for about 80% of all cases of the disease. The remaining cases consist of inherited tumor syndromes, such as: 1) MEN type 2A (MEN2A), which is the most common type; and 2) MEN2B.427,428 Familial MTC is now viewed as a variant of MEN2A.423,424,429 Sporadic disease typically presents in the fifth or sixth decade of life. Inherited forms of the disease tend to present at earlier ages.423,424 The 5-year relative survival for stages I to III is about 93%, whereas 5-year survival for stage IV is about 28%.168,189 Because the C cells are predominantly located in the upper portion of each thyroid lobe, patients with sporadic disease typically present with upper pole nodules. Metastatic cervical adenopathy appears in about 50% of patients at initial presentation. Symptoms of upper aerodigestive tract compression or invasion are reported by up to 15% of patients with sporadic disease.430 Distant metastases in the lungs or bones cause symptoms in 5% to 10% of patients. Many patients with advanced MTC can have diarrhea, Cushing syndrome, or facial flushing, because the tumor can secrete calcitonin and sometimes other hormonally active peptides (ie, adrenocorticotropic hormone [ACTH], calcitonin gene-related peptide [CGRP]). Treatment with somatostatin analogs (eg, octreotide, lanreotide) may be useful in patients with these symptoms.431 Patients with unresectable or metastatic disease may have either slowly progressive or rapidly progressive disease. Nodule Evaluation and Diagnosis Patients with MTC can be identified by using pathologic diagnosis or by prospective genetic screening. Separate pathways are included in the algorithm (see Clinical Presentation in the NCCN Guidelines for Medullary [Thyroid] Carcinoma) depending on the method of identification. Sporadic MTC Sporadic MTC is usually suspected after FNA of a solitary nodule (see Nodule Evaluation in the NCCN Guidelines for Thyroid Carcinoma). Reports suggest that about 3% of patients with nodular thyroid disease will have an increased serum calcitonin level when measured by a sensitive immunometric assay; 40% of these patients will have MTC at thyroidectomy.432-434 However, routine measurement of the basal serum calcitonin concentration is not recommended by the NCCN Panel for evaluating a patient with nodular thyroid disease because of: 1) the expense of screening all thyroid nodules and only finding a few cases of MTC; 2) the lack of confirmatory pentagastrin stimulation testing; and 3) Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 96. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-30 the resulting need for thyroidectomy in some patients who have benign thyroid disease.435,436 The ATA is equivocal about routine calcitonin measurement.3 Inherited MTC For patients with known kindreds with inherited MTC, prospective family screening with testing for mutant RET genes can identify disease carriers long before clinical symptoms or signs are noted.425,426 The traditional approach of stimulating secretion of calcitonin by either pentagastrin or calcium infusion to identify patients with MTC is no longer recommended, because elevated calcitonin is not a specific or adequately sensitive marker for MTC437 and because pentagastrin is no longer available in the United States. When MEN2A is suspected, the NCCN Guidelines recommend measurement of calcium levels with (or without) serum intact parathyroid hormone levels (see Additional Workup in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Compared with sporadic disease, the typical age of presentation for familial disease is the third or fourth decade of life, without gender preference. In patients with MEN2A, signs or symptoms of hyperparathyroidism or pheochromocytoma rarely present before those of MTC, even in the absence of screening. All familial forms of MTC and MEN2 are inherited in an autosomal-dominant fashion. Mutations in the RET proto-oncogene are found in at least 95% of kindreds with MEN2A and 88% of cases of familial MTC.425,426,438 The RET proto-oncogene codes for a cell membrane-associated tyrosine kinase receptor for a glial, cell line-derived neurotrophic factor. Mutations associated with MEN2A and familial MTC have been primarily identified in several codons of the cysteine-rich extracellular domains of exons 10, 11, and 13; MEN2B and some familial MTC mutations are found within the intracellular exons 14 to 16.423,424 Somatic mutations in exons 11, 13, and 16 have also been found in at least 25% of sporadic MTC tumors—particularly the codon 918 mutation that activates the tyrosine kinase function of the receptor—and are associated with poorer prognosis of the patient. About 6% of patients with clinically sporadic MTC carry a germline RET mutation, leading to identification of new kindreds with multiple (previously undiagnosed) affected individuals.439,440 Germline testing for RET proto-oncogene mutations with genetic counseling by a physician or genetic counselor is recommended for all patients with newly diagnosed, clinically apparent, sporadic MTC.441 If a germline RET mutation is found, then mutation testing should also be done for family members. MTC can involve difficult ethical decisions for clinicians if parents or guardians refuse screening and/or treatment for children with possible MTC.442 Principles regarding genetic risk assessment can be found in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (available at www.NCCN.org). The generally accepted preoperative workup includes measurement of serum markers (basal serum calcitonin and serum carcinoembryonic antigen [CEA]) and screening of patients with germline RET proto-oncogene mutations for pheochromocytoma (MEN2A and MEN2B) and hyperparathyroidism (MEN2A). Before surgery for MTC, it is important to diagnose and address coexisting pheochromocytoma to avoid hypertensive crisis during surgery (see Pheochromocytoma/Paraganglioma in the NCCN Guidelines for Neuroendocrine Tumors, available at www.NCCN.org). Pheochromocytoma can be removed using laparoscopic adrenalectomy.423,424,443 Preoperative thyroid and neck ultrasound (including central and lateral neck compartments) is recommended. Contrast-enhanced CT of neck/chest and liver MRI or 3-phase CT of liver can be considered as clinically indicated, such as in cases of high burden of disease, calcitonin greater than 400 pg/mL, or elevated CEA levels. Distant metastasis does not contraindicate surgery.423,424 Liver imaging is Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 97. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-31 rarely needed if calcitonin is less than 400 pg/mL. Evaluation of vocal cord mobility can also be considered for patients with abnormal voice, surgical history involving the recurrent laryngeal or vagus nerves, invasive disease, or bulky disease of the central neck. Staging As previously mentioned, the NCCN Guidelines for Thyroid Carcinoma do not use TNM stages to guide therapy. Instead, many characteristics of the tumor and patient play important roles in these NCCN Guidelines. Many specialists in thyroid cancer also follow this paradigm. The TNM criteria for clinicopathologic tumor staging are based on tumor size, the presence or absence of extrathyroidal invasion, locoregional nodal metastases, and distant metastases (see Table 1 in the NCCN Guidelines for Thyroid Carcinoma).10 The 8th edition of the AJCC Cancer Staging Manual separated MTC into its own stand-alone chapter.10 Many of the studies cited in this Discussion reporting on AJCC-TNM staging have referred to the 5th edition of the AJCC-TNM staging187 and not to the 6th , 7th , or 8th editions.10,188,189 However, the TNM staging classification lacks other important prognostic factors.444 Notably absent is the age at diagnosis. Patients younger than 40 years at diagnosis have a 5- and 10-year disease-specific survival rate of about 95% and 75%, respectively, compared with 65% and 50% for those older than 40 years.430,444 Controlling for the effect of age at diagnosis, the prognosis of patients with inherited disease (who typically are diagnosed at an earlier age) is probably similar to those with sporadic disease.445,446 Despite an even younger typical age at diagnosis, however, patients with MEN2B who have MTC are more likely than those with MEN2A (or familial MTC) to have locally aggressive disease.446 Other factors that may be important for predicting a worse prognosis include: 1) the heterogeneity and paucity of calcitonin immunostaining of the tumor447 ; 2) a rapidly increasing CEA level, particularly in the setting of a stable calcitonin level448 ; and 3) postoperative residual hypercalcitoninemia.449 A study comparing different staging systems found that a system incorporating age, gender, and distant metastases (EORTC) had the greatest predictive value; however, the AJCC staging system was deemed to be the most appropriate.444,450 Codon analysis is useful for predicting prognosis.423,424,451 Presence of an exon 16 mutation, either within a sporadic tumor or associated with MEN2B, is associated with more aggressive disease.452 More than 95% of patients with MEN2B have a mutation in exon 16 (codon 918), whereas 2% to 3% have a mutation in exon 15 (codon 883).453 Surgical Management Surgery is the main treatment for MTC. While no curative systemic therapy for MTC is available, vandetanib and cabozantinib are recommended for locally advanced and metastatic MTC (see Recurrent or Persistent Disease in this Discussion).454-457 MTC cells do not concentrate RAI, and MTC does not respond well to conventional cytotoxic chemotherapy. Therefore, iodine-131 imaging cannot be used, and RAI treatment is not effective in these patients. Postoperative levothyroxine is indicated for all patients; however, TSH suppression is not appropriate because C cells lack TSH receptors. Thus, TSH should be kept in the normal range by adjusting the levothyroxine dose.423,424 Patients should be assessed for hyperparathyroidism and pheochromocytoma preoperatively, even in patients who have apparently sporadic disease, because the possibility of MEN2 should dictate testing for a germline RET proto-oncogene mutation for all patients with MTC. Pheochromocytomas should be removed (eg, laparoscopic adrenalectomy) before surgery on the thyroid to avoid hypertensive crisis during surgery (see Pheochromocytoma/Paraganglioma in the NCCN Guidelines for Neuroendocrine Tumors, available at www.NCCN.org). Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 98. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-32 Patients with pheochromocytomas must be treated preoperatively with alpha-adrenergic blockade (phenoxybenzamine) or with alpha-methyltyrosine to avoid a hypertensive crisis during surgery. Forced hydration and alpha-blockade are necessary to prevent hypotension after the tumor is removed. After institution of alpha-blockade and hydration, beta-adrenergic blockade may be necessary to treat tachyarrhythmia. Total thyroidectomy and bilateral central neck dissection (level VI) are indicated in all patients with MTC whose tumor is 1 cm or larger or who have bilateral thyroid disease; total thyroidectomy is recommended and neck dissection can be considered for those whose tumor is smaller than 1 cm and for unilateral thyroid disease (see Primary Treatment in the NCCN Guidelines for Medullary [Thyroid] Carcinoma).374,430 Given the risks of thyroidectomy in very young children, referral to a surgeon and team with experience in pediatric thyroid surgery is advised. If a patient with inherited disease is diagnosed early enough, the recommendation is to perform a prophylactic total thyroidectomy by age 5 years or when the mutation is identified (in older patients), especially in patients with codon 609, 611, 618, 620, 630, or 634 RET mutations.423,424,458 Note that C634 mutations are the most common mutations.423,424 Total thyroidectomy is recommended in the first year of life or at diagnosis for patients with MEN2B who have codon 883 RET mutations, 918 RET mutations, or compound heterozygous (V804M + E805K, V804M + Y806C, or V804M + S904C) RET mutations (see Clinical Presentation in the NCCN Guidelines for Medullary [Thyroid] Carcinoma), because these RET mutations carry the highest risk for MTC (ie, level D).423,424,459 However, for patients with codon 768, 790, 791, 804, and 891 RET (risk level A) mutations, the lethality of MTC may be lower than with other RET mutations.423,424,459,460 In patients with these less high-risk (ie, lower-risk level A) RET mutations, annual basal calcitonin testing and annual ultrasound are recommended; total thyroidectomy and central node dissection may be deferred if these tests are normal, there is no family history of aggressive MTC, and the family agrees to defer surgery (see Additional Workup in the NCCN Guidelines for Medullary [Thyroid] Carcinoma).423,424,461,462 Delaying thyroidectomy may also be appropriate for children with lower-risk mutations (ie, level A) because of the late onset of MTC development.423,424,460,461,463 A study found no evidence of persistent or recurrent MTC 5 years or more after prophylactic total thyroidectomy in young patients with RET mutations for MEN2A; longer follow-up is necessary to determine if these patients are cured.464 Variations in surgical strategy for MTC depend on the risk for locoregional node metastases and on whether simultaneous parathyroid resection for hyperparathyroidism is necessary.423,424 A bilateral central neck dissection (level VI) can be considered for all patients with MEN2B. For those patients with MEN2A who undergo prophylactic thyroidectomy, therapeutic ipsilateral or bilateral central neck dissection (level VI) is recommended if patients have an increased calcitonin or CEA test or if ultrasound shows a thyroid or nodal abnormality. Similarly, more extensive lymph node dissection (levels II–V) is considered for these patients with primary tumor(s) 1 cm or larger in diameter (0.5 cm for patients with MEN2B) or for patients with central compartment lymph node metastases (see Primary Treatment in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). With a concurrent diagnosis of hyperparathyroidism in MEN2A or familial MTC, the surgeon should leave or autotransplant the equivalent mass of one normal parathyroid gland if multiglandular hyperplasia is present. Cryopreservation of resected parathyroid tissue should be considered to allow future implantation in the event of iatrogenic hypoparathyroidism. Disfiguring radical node dissections do not improve prognosis and are not indicated. In the presence of grossly invasive disease, more extended Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 99. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-33 procedures with resection of involved neck structures may be appropriate. Function-preserving approaches are preferred. In some patients, MTC is diagnosed after thyroid surgery. In these patients, additional workup is recommended to ascertain whether they have RET proto-oncogene mutations (eg, exons 10, 11, 13–16), which will determine whether they need additional surgery (eg, completion thyroidectomy and/or neck dissection) (see Additional Workup in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Adjuvant RT EBRT and IMRT have not been adequately studied as adjuvant therapy in MTC.301,423,465 Slight improvements in local DFS have been reported after EBRT for selected patients, such as those with extrathyroidal invasion or extensive locoregional node involvement.466 However, most centers do not have extensive experience with adjuvant EBRT or IMRT for this disease. While therapeutic EBRT or IMRT may be considered for grossly incomplete resection when additional attempts at surgical resection have been ruled out, adjuvant EBRT or IMRT is rarely recommended (see Primary Treatment in the NCCN Guidelines for Medullary [Thyroid] Carcinoma).423,424 EBRT or IMRT can also be given to palliate painful or progressing bone metastases.303,304,401,423,424 There is little evidence regarding appropriate treatment volumes for use of RT for MTC, but guidance regarding EBRT dose and fractionation is provided in the Principles of Radiation and Radioactive Iodine Therapy: External Beam Radiation Therapy in the NCCN Guidelines for Thyroid Carcinoma. Persistently Increased Calcitonin Basal serum concentrations of calcitonin and CEA should be measured 2 or 3 months postoperatively. About 80% of patients with palpable MTC and 50% of those with nonpalpable but macroscopic MTC who undergo supposedly curative resection have serum calcitonin values indicative of residual disease. Those patients with residual disease may benefit from further evaluation to detect either residual resectable disease in the neck or the presence of distant metastases. Patients with detectable basal calcitonin or elevated CEA who have negative imaging and who are asymptomatic may be followed (see Surveillance in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Patients with a basal serum calcitonin value greater than 1000 pg/mL—and with no obvious MTC in the neck and upper mediastinum—probably have distant metastases, most likely in the liver. However, occasionally patients have relatively low serum CEA and calcitonin levels but have extensive metastatic disease; initial postoperative imaging is therefore reasonable despite the absence of very high serum markers. The prognosis for patients with postoperative hypercalcitoninemia depends primarily on the extent of disease at the time of initial surgery. In a study of 31 patients (10 patients with apparently sporadic disease, 15 patients with MEN2A, and 6 patients with MEN2B), the 5- and 10-year survival rates were 90% and 86%, respectively.467 Two studies have reported higher mortality rates for patients with high postoperative serum calcitonin values, with more than 50% of patients having a recurrence during a mean follow-up of 10 years.449,468 Routine lymphadenectomy or excision of palpable tumor generally fails to normalize the serum calcitonin concentrations in such patients; therefore, some have focused on detection and eradication of microscopic tumor deposits with a curative intent in patients without distant metastases. Extensive dissection to remove all nodal and perinodal tissue from the neck and upper mediastinum was first reported to normalize the serum calcitonin levels in 4 of 11 patients at least 2 years postoperatively.469 In subsequent larger studies, 20% to 40% of patients undergoing microdissection of the central and bilateral neck compartments were biochemically cured, with minimal perioperative morbidity.470,471 When repeat surgery is planned for curative intent, preoperative assessment should include locoregional imaging (ie, ultrasonography of the neck and upper mediastinum) and attempts to Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 100. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-34 exclude patients with distant metastases, which may include contrast-enhanced CT or MRI of the neck, chest, and abdomen.471 Postoperative Management and Surveillance Calcitonin is very useful for surveillance, because this hormone is only produced in the parafollicular cells. Thus, measurements of serum calcitonin and CEA levels are the cornerstone of postoperative assessment for residual disease (see Management 2–3 Months Postoperative in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). For patients with a detectable basal calcitonin or elevated CEA level, neck ultrasound is recommended. Patients with undetectable calcitonin levels and normal CEA levels can subsequently be followed with annual measurements of serum markers. Additional studies or more frequent testing can be done for those with significantly rising calcitonin or CEA. Nonetheless, the likelihood of significant residual disease is very low in patients with an undetectable basal calcitonin level in a sensitive assay. If the patient has MEN2, annual screening for pheochromocytoma (MEN2B or MEN2A) and hyperparathyroidism (MEN2A) should also be performed. For some low-risk RET mutations (eg, codons 768, 790, 804, or 891), less frequent screening may be appropriate. Patients with detectable serum markers (ie, calcitonin levels ≥150 pg/mL) should have CT or MRI of the neck, chest, and liver. Bone scan and MRI of axial skeleton should be considered in select patients such as those with very elevated calcitonin levels.423,424 The NCCN Panel recognizes that many different imaging modalities may be used to examine for residual or metastatic tumor, but there is insufficient evidence to recommend any particular choice or combination of tests.423,424 For patients with asymptomatic disease and detectable markers in whom imaging fails to identify foci of disease, the NCCN Panel recommends conservative surveillance with repeat measurement of the serum markers every 6 to 12 months. Additional imaging studies (eg, FDG PET/CT, Ga- 68 DOTATATE, or MRI with contrast of the neck, chest, and abdomen with liver protocol) may be indicated depending on calcitonin/CEA doubling time. For patients who are asymptomatic with abnormal markers and repeated negative imaging, continued disease monitoring or consideration of cervical reoperation is recommended if primary surgery was incomplete. For the patient with increasing serum markers, more frequent imaging may be considered. Outside of clinical trials, no therapeutic intervention is recommended on the basis of abnormal markers alone. Recurrent or Persistent Disease Kinase inhibitors may be appropriate for select patients with recurrent or persistent MTC that is not resectable (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Although kinase inhibitors may be recommended for patients with MTC, it is important to note that kinase inhibitors may not be appropriate for patients with stable or slowly progressing indolent disease.321,472,473 Vandetanib and cabozantinib are oral receptor kinase inhibitors that increase PFS in patients with metastatic MTC.454,457,474-476 RET inhibitors that are FDA- approved for RET-mutated MTC include selpercatinib and pralsetinib.350,351 Vandetanib is a multitargeted kinase inhibitor; it inhibits RET, VEGFR, and endothelial growth factor receptor (EGFR).454 In a phase III randomized trial in patients with unresectable, locally advanced, or metastatic MTC (n = 331), vandetanib increased PFS when compared with placebo (HR, 0.46; 95% CI, 0.31–0.69; P .001); OS data are not yet available.454 A post-hoc subgroup analysis including 184 patients with symptomatic and progressive disease at baseline also showed increased PFS (HR, 0.43; 95% CI, 0.28–0.64; P .001) in patients who received vandetanib, compared to the placebo, although time to worsening pain was not significantly different between the two groups (HR, 0.67; 95% CI, 0.43– 1.04; P = .07).477 In this subgroup, the overall response rate (ORR) was Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 101. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-35 37% in the patients who received vandetanib and 2% in patients who received the placebo (P .001). The FDA approved the use of vandetanib for patients with locally advanced or metastatic MTC who are not eligible for surgery and whose disease is causing symptoms or growing.455 However, access is restricted through a vandetanib Risk Evaluation and Mitigation Strategy (REMS) program because of potential cardiac toxicity.478 The NCCN Panel recommends vandetanib (category 1) as a preferred option for patients with recurrent or persistent MTC (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Cabozantinib is a multitargeted kinase inhibitor that inhibits RET, VEGFR2, and MET. In a phase 3 randomized trial (EXAM) in patients with locally advanced or metastatic MTC (n = 330), cabozantinib increased median PFS when compared with placebo (11.2 vs. 4.0 months; HR, 0.28; 95% CI, 0.19–0.40; P .001).457 Following long-term follow-up, the median OS for patients treated with cabozantinib was 26.6 months compared to 21.1 months for placebo, although this difference was not statistically significant (stratified HR, 0.85; 95% CI, .64–1.12, P = .24).479 Exploratory analyses have suggested that cabozantinib may have a greater clinical benefit for medullary thyroid cancers harboring RET M918T or RAS mutations, although prospective trials are needed to confirm.479,480 In 2012, the FDA approved the use of cabozantinib for patients with progressive, metastatic MTC.456 The NCCN Panel recommends cabozantinib (category 1) as a preferred option based on the phase III randomized trial and FDA approval (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Rare adverse events with cabozantinib include severe bleeding and gastrointestinal perforations or fistulas; severe hemorrhage is a contraindication for cabozantinib. RET mutations account for a significant percentage of MTC cases,481,482 supporting investigation into the impact of recently developed RET inhibitors on RET-mutated MTC. The phase I–II LIBRETTO-001 study evaluated the efficacy of the RET inhibitor selpercatinib in 143 patients with RET-mutant MTC.350 In patients previously treated with vandetanib or cabozantinib (n = 55), the ORR and 1-year PFS rates were 69% (95% CI, 55%–81%) and 82% (95% CI, 69%–90%), respectively. In patients with no previous vandetanib or cabozantinib treatment (n = 88), the ORR and 1- year PFS rates were 73% (95% CI, 62%–82%) and 92% (95% CI, 82%– 97%), respectively. The most commonly reported toxicities (grade 3 and 4) were hypertension (21%), increased alanine aminotransferase (11%), increased aspartate aminotransferase (9%), hyponatremia (8%), and diarrhea (6%). Dose reductions due to treatment-related adverse events were reported in 30% of patients. Pralsetinib, another RET inhibitor, was evaluated in the phase I–II ARROW study, which included 92 patients with RET-mutant MTC.483 The ORR was 60% (95% CI, 46%–74%) in patients previously treated with vandetanib or cabozantinib (n = 61) and 74% (95% CI, 49%–91%) in patients with no previous vandetanib or cabozantinib treatment (n = 22). Pralsetinib was generally well-tolerated, with the most commonly reported grade 3–4 treatment-related adverse events being hypertension (11%) and neutropenia (10%). These results are currently reported in abstract form, and the ARROW study is ongoing and continuing to enroll patients. In 2020, the FDA approved both of these RET inhibitors for RET-mutated MTC requiring systemic therapy. Based on the data and the FDA approvals, the NCCN Panel recommends selpercatinib and pralsetinib as preferred options for patients with RET- mutant disease (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). RET somatic genotyping may be done in patients who are germline wild-type or if germline status is unknown. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 102. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-36 When locoregional disease is identified in the absence of distant metastases, surgical resection is recommended with (or without) postoperative EBRT or IMRT. For unresectable locoregional disease that is symptomatic or progressing by Response Evaluation Criteria in Solid Tumors (RECIST) criteria,484 the following options can be considered: 1) RT (EBRT or IMRT); or 2) systemic therapy. Treatment can be considered for symptomatic distant metastases (eg, those in bone); recommended options include: 1) palliative resection, ablation (eg, radiofrequency, embolization), or other regional treatment; 2) vandetanib (category 1); or 3) cabozantinib (category 1) (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). These interventions may be considered for asymptomatic distant metastases (especially for progressive disease), but disease monitoring is acceptable given the lack of data regarding alteration in outcome. If systemic therapy is indicated, then vandetanib and cabozantinib are category 1 preferred options. Selpercatinib or pralsetinib are preferred options for patients with RET- mutation positive disease. Pembrolizumab is also an option for patients with TMB-H (≥10 mut/Mb) disease, based on results of the phase II KEYNOTE-158 trial, which included two patients with thyroid cancer.352 The NCCN Panel does not recommend treatment with systemic therapy for increasing calcitonin or CEA alone. In the setting of symptomatic disease or progression, the NCCN Panel recommends systemic therapy or enrollment in a clinical trial. As stated above for locoregional disease, preferred systemic therapy options include vandetanib (category 1), cabozantinib (category 1), and selpercatinib or pralsetinib for patients with RET-mutation positive disease. Other small- molecule kinase inhibitors (ie, sorafenib, sunitinib, lenvatinib, pazopanib) may be considered if clinical trials or the NCCN-preferred systemic therapy options are not available or are not appropriate.334,485-490 If the patient progresses on a preferred option, then systemic chemotherapy can be administered using dacarbazine or combinations including dacarbazine.423,491-493 Pembrolizumab is also an option for patients with TMB-H (≥10 mut/Mb) disease (useful in certain circumstances).352 EBRT or IMRT can be used for local symptoms. Intravenous bisphosphonate therapy or denosumab can be considered for bone metastases.402-404 Best supportive care is also recommended. Results from clinical trials have shown the effectiveness of novel multitargeted therapies including sunitinib,334,335 sorafenib,412,486 lenvatinib,489 and pazopanib488 in MTC. Severe or fatal side effects from kinase inhibitors include bleeding, hypertension, and liver toxicity; however, many side effects can be managed.362,365,408,413 Because some patients may have indolent and asymptomatic disease, potentially toxic therapy may not be appropriate.362 Novel therapies and the management of aggressive MTC have been reviewed.315,423,494-497 Of interest, calcitonin levels decreased dramatically after vandetanib therapy, which did not directly correlate with changes in tumor volume; thus, calcitonin may not be a reliable marker of tumor response in patients receiving RET inhibitor therapy.498 A phase 2 trial in patients with progressive metastatic MTC assessed treatment using pretargeted anti–CEA radioimmunotherapy with iodine-131.499 OS was improved in the subset of patients with increased calcitonin doubling times.500 Anaplastic Thyroid Carcinoma ATCs are aggressive undifferentiated tumors, with a disease-specific mortality approaching 100%.501 Patients with anaplastic carcinoma are older than those with differentiated carcinomas, with a mean age at diagnosis of approximately 71 years.502 Fewer than 10% of patients are younger than 50 years, and 60% to 70% of patients are women.108,502 The incidence of ATC is decreasing because of better management of differentiated thyroid cancer and because of increased iodine in the Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 103. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-37 diet.501,503 As previously mentioned, anaplastic carcinoma is the least common type of thyroid carcinoma. An average of 63,229 patients/year were diagnosed with thyroid carcinoma between 2010 to 2014. Of these 63,229 patients, only 514 patients (0.8%) had anaplastic carcinoma.31 Approximately 50% of patients with ATC have either a prior or coexistent differentiated carcinoma. Anaplastic carcinoma develops from more differentiated tumors as a result of one or more dedifferentiating steps, particularly loss of the p53 tumor suppressor protein.504 No precipitating events have been identified, and the mechanisms leading to anaplastic transformation of differentiated carcinomas are uncertain. Iodine deficiency is associated with ATC. More than 80% of patients with ATC have a history of goiter.503,505,506 Differentiated thyroid carcinomas can concentrate iodine, express TSH receptor, and produce Tg, whereas poorly differentiated or undifferentiated carcinomas typically do not. Therefore, iodine-131 imaging cannot be used. ATC is typically diagnosed based on clinical symptoms, unlike differentiated thyroid carcinoma, which is typically diagnosed after FNA on a suspicious thyroid nodule. Patients with ATC may present with symptoms such as rapidly enlarging neck mass, dyspnea, dysphagia, neck pain, Horner syndrome, stroke, and hoarseness due to vocal cord paralysis.507 Patients with ATC present with extensive local invasion, and distant metastases are found at initial disease presentation in 15% to 50% of patients.508,509 The lungs and pleura are the most common sites of distant metastases (≤90% of patients with distant disease). About 5% to 15% of patients have bone metastases; 5% have brain metastases; and a few have metastases to the skin, liver, kidneys, pancreas, heart, and adrenal glands. Diagnosis The diagnosis of ATC is usually established by core or surgical biopsy. If FNA is suspicious or not definitive, core or surgical biopsy should be performed to establish the diagnosis of ATC.510 The appearance of ATCs varies widely; many ATCs have mixed morphologies. The most common morphology is biphasic spindle and giant cell tumor. Sometimes it is difficult to discriminate between ATC and other primary thyroid malignancies (ie, MTC, thyroid lymphoma) or poorly differentiated cancer metastatic to the thyroid.95,510 Diagnostic procedures include a complete blood count (CBC) with differential, comprehensive metabolic panel, TSH level, direct exam of larynx with evaluation of vocal cord mobility, and imaging studies. Neck ultrasound can rapidly assess tumor extension and invasion.507 CT scans of the head, neck, chest, abdomen, and pelvis can accurately determine the extent of the thyroid tumor and identify tumor invasion of the great vessels and upper aerodigestive tract structures.511 PET/CT or MRI scans are recommended to accurately stage the patient. Bone metastases are usually lytic. All ATCs are considered stage IV (A, B, or C) (see Table 1 in the NCCN Guidelines for Thyroid Carcinoma).10 Clinically apparent anaplastic tumors are usually unresectable. Given the increasing number of therapeutic targets for ATC, tumor testing for actionable mutations (BRAF, NTRK, ALK, RET, MSI, dMMR, and TMB) is recommended (see below in the Discussion under Treatment: Systemic Therapy). 510 Prognosis No curative therapy exists for ATC; it is almost uniformly fatal.512,513 The median survival from diagnosis is about 5 months.503,514 The 1-year survival rate is about 20%.509,514 Death is attributable to upper airway obstruction and suffocation (often despite tracheostomy) in 50% of these patients; in the remaining patients, death is attributable to complications of local and distant disease and/or therapy.515 Patients with disease confined Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 104. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-38 to the neck at diagnosis have a mean survival of 8 months compared with 3 months if the disease extends beyond the neck.516 Other variables that may predict a worse prognosis include older age at diagnosis, distant metastases, white blood cell (WBC) count greater than or equal to 10,000 mm3 , and dyspnea as a presenting symptom.517,518 A retrospective cohort study conducted at an NCCN Member Institution, including 479 patients diagnosed with ATC between 2000 and 2019, showed that survival rates for this disease are increasing.519 Treatment factors associated with increased survival in this sample included use of targeted therapy with or without immunotherapy, and neoadjuvant BRAF-targeted therapy followed by surgery. Treatment ATC has a very poor prognosis and responds poorly to conventional therapy. RAI treatment is not effective in these patients.510 The role of palliative and supportive care is paramount and should be initiated early in the disease.510 At the outset of the diagnosis, it is critical that conversations about end-of-life care be initiated so that a clear understanding of how to manage the airway is undertaken, which is clear to the family and all providers. Tracheostomy is often a morbid and temporary treatment of the airway and may not be the option a patient would choose.515,520 Surgery Once the diagnosis of ATC is confirmed, it is essential to rapidly determine whether local resection is an option.501 Before resection is attempted, the extent of disease—particularly in the larynx, trachea, and neck—should be accurately assessed by a very experienced surgeon who is capable of performing extensive neck dissections, if necessary. However, most patients with ATC have unresectable or metastatic disease. The patency of the airway should be assessed throughout the patient’s course of treatment.515 If the patient appears to have resectable disease, an attempt at total thyroidectomy with complete gross tumor resection should be made, with selective resection of all involved local or regional structures and nodes.510 Total thyroidectomy with attempted complete tumor resection has not been shown to prolong survival except for the few patients whose tumors are small and confined entirely to the thyroid or readily excised structures.514,516,521,522 Patients need to receive levothyroxine if total thyroidectomy is done. Tracheostomy may be considered in patients with stage IVc disease. Radiation Therapy EBRT or IMRT can increase short-term survival in some patients; EBRT or IMRT can also improve local control and can be used for palliation (eg, to prevent asphyxiation).465,501,510,518,523-527 Adjuvant RT, especially when combined with concurrent chemotherapy, is associated with improved survival.528 Higher RT dose is associated with OS in patients with unresected ATC.529 Surgical excision or external irradiation should be considered for isolated skeletal metastases. For solitary brain lesions, either neurosurgical resection or RT is recommended. Once brain metastases are diagnosed, disease-specific mortality is very high, with a reported median survival of 1.3 months. For unresected or incompletely resected disease, RT should commence as quickly as possible. For R0 or R1 resection, adjuvant RT should begin as soon as the patient has sufficiently recovered from surgery, ideally 2 to 3 weeks postoperatively. Enteral nutrition may be useful for some patients who have difficulty swallowing (see Principles of Nutrition: Management and Supportive Care in the NCCN Guidelines for Head and Neck Cancer, available at www.NCCN.org). If enteral feeding is considered, a careful conversation should occur with the patient about their wishes. For guidance regarding appropriate treatment volumes for use of RT for ATC, see the Principles of Radiation and Radioactive Iodine Therapy: External Beam Radiation Therapy in the NCCN Guidelines for Thyroid Carcinoma. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 105. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-39 Systemic Therapy Systemic therapy recommendations are described in the algorithm (see Systemic Therapy for Anaplastic Thyroid Carcinoma in the NCCN Guidelines for Anaplastic [Thyroid] Carcinoma). When systemic therapy is indicated, targeted therapy options are preferred. Dabrafenib plus trametinib combination is an option for BRAF V600E mutation-positive tumors,530 larotrectinib or entrectinib are options for NTRK gene fusion- positive tumors,348,349,531 selpercatinib or pralsetinib are options for RET fusion-positive disease,350,351 and pembrolizumab is an option for TMB-H (≥10 mut/Mb) disease.352 Other recommended regimens include paclitaxel and doxorubicin monotherapies.510 Doxorubicin combined with cisplatin is an option based on a small randomized trial.532 Paclitaxel combined with carboplatin and docetaxel combined with doxorubicin are also systemic therapy options for patients with metastatic ATC, but these are category 2B options based on low-quality evidence510 and less panel consensus. The NCCN Panel recommends molecular testing to help inform decisions regarding systemic therapy and to determine eligibility for clinical trials. The dosage and frequency of administration of all the recommended systemic therapy agents are provided in the algorithm. Either concurrent chemoradiation or chemotherapy alone regimens may be used depending on the clinical setting; however, chemoradiation is generally more toxic. If using chemoradiation, the ATA Guidelines recommend using weekly chemotherapy regimens.510 A phase 2, open-label trial of 16 patients with BRAF V600E-mutated ATC evaluated the efficacy and safety of dabrafenib 150 mg, twice daily, in combination with trametinib 2 mg, once daily.530 The confirmed ORR was 69% (95% CI, 41%–89%), with seven responses ongoing. While duration of response, PFS, and OS were not yet reached, the 12-month estimates were 90%, 79%, and 80%, respectively. The combination was found to be well-tolerated as evaluated in 100 patients across seven rare tumor types; common adverse events included fatigue (38%), pyrexia (37%), and nausea (35%).530 Based on these data, the FDA approved dabrafenib/trametinib for ATC with BRAF V600E mutation in 2018. A pooled analysis of three studies (a phase 1 including adults, a phase 1/2 involving children, and a phase 2 involving adolescents and adults) studied the safety and efficacy of larotrectinib in patients with NTRK gene fusion-positive tumors, including seven patients with thyroid cancer of which one patient had ATC.348,533 For the whole population, the ORR was 75% (95% CI, 61%–85%) by independent review and 80% (95% CI, 67%– 90%) by investigator assessment.348,533 One hundred percent of the thyroid cancers in this study responded to larotrectinib, with one complete response and four partial responses.533 Larotrectinib was found to be well- tolerated, as the majority (93%) of adverse events were grades 1 or 2 and no treatment-related adverse events of grades 3 or 4 occurred in more than 5% of patients.348 A pooled analysis from a phase II trial and two phase I trials including 54 patients with NTRK gene fusion-positive cancer (9% having thyroid cancer) showed an objective response rate of 57.4% for entrectinib, another TRK inhibitor.349 Based on these data, the FDA approved larotrectinib and entrectinib for treatment of patients with NTRK gene fusion-positive tumors, and the panel also recommends NTRK therapy options such as larotrectinib or entrectinib for patients with NTRK gene fusion-positive metastatic ATC. The phase I–II LIBRETTO-001 study evaluated the efficacy of the RET inhibitor selpercatinib in 19 patients with previously treated RET fusion- positive thyroid cancer (2 patients with anaplastic disease).350 The ORR was 79% (95% CI, 54%–94%), and 1-year PFS was 64% (95% CI, 37%– 82%). In the ongoing phase I–II ARROW study, pralsetinib, another RET inhibitor, is being evaluated in patients with RET fusion-positive disease (NCT03037385). In an analysis including 9 patients with RET fusion- positive thyroid cancer, the ORR was 89% (95% CI, 52%–100%) with Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 106. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-40 durable responses (100% DCR).351 In 2020, the FDA approved both of these RET inhibitors for RAI-refractory RET fusion-positive thyroid cancer requiring systemic therapy. The FDA approved the anti-PD-1 antibody pembrolizumab for treatment of previously treated TMB-H (≥10 mut/Mb) solid tumors in 2020 based on results of the phase II KEYNOTE-158 trial, which included two patients with thyroid cancer.352 For the whole sample, the ORR was 29% (95% CI, 21%–39%). Grade 3–5 treatment-related adverse events were reported in 15% of the patients. A phase II study evaluated another anti-PD-1 antibody, spartalizumab, in 42 patients with locally advanced or metastatic ATC.534 The ORR was only 19% (95% CI, 8.6%–34.1%), but was higher for patients with PD-L1–positive disease (29%; 95% CI, 13.2%–48.7%) and highest in patients with PD-L1 greater than 50% (35%; 95% CI, 14.2%–61.7%). Treatment with anthracyclines and taxanes is generally not very effective for advanced anaplastic disease, although some patients may show disease response or have stable disease.510,527 Single-agent doxorubicin is approved by the FDA for ATC. A randomized trial including 84 patients with advanced thyroid cancer (not limited to ATC) showed an 11.6% complete response rate in patients who received doxorubicin combined with cisplatin, compared to a complete response in 0 patients who received single-agent doxorubicin.532 ORR did not differ significantly between the study arms (26% vs. 17%, respectively). Single-agent paclitaxel may benefit some patients with newly diagnosed ATC; increased survival has been reported in patients with stage IVB disease.535-537 If weekly paclitaxel is used, the ATA Guidelines510 recommend using paclitaxel at 60 to 90 mg/m2 IV weekly and not the dose previously reported in the study by Ain et al.537 Given the poor outcome with current standard therapy, all patients— regardless of surgical resection—should be considered for clinical trials. Previous clinical trials for ATC have tested therapies including fosbretabulin (and its parent drug, combretastatin A4 phosphate [CA4P], and crolibulin [EPC2407], which are vascular disrupting agents), efatutazone (an oral PPAR gamma agonist), and novel multitargeted therapies including bevacizumab with doxorubicin, sorafenib, sunitinib, imatinib, and pazopanib.335,538-546 A trial in 80 patients (FACT) reported that the addition of fosbretabulin—to a carboplatin/paclitaxel regimen—resulted in a nonsignificant increase in median survival (5.2 vs. 4.0 months).538,547 Preliminary data suggest that ALK inhibitors may be effective in a subset of patients with papillary thyroid cancer who have ALK gene fusions; however, these ALK gene fusions are rarely reported in patients with ATC.353-356 Hyperfractionated EBRT, combined with radiosensitizing doses of doxorubicin, may increase the local response rate to about 80%, with a subsequent median survival of 1 year.548 Distant metastases then become the leading cause of death.549 Similar improvement in local disease control has been reported with a combination of hyperfractionated RT and doxorubicin-based regimens, followed by debulking surgery in responsive patients or other multimodality approaches.527,550-552 IMRT may be useful to reduce toxicity.465,510,553-557 However, the addition of larger doses of other chemotherapeutic drugs has not been associated with improved control of distant disease or with improved survival. Other radiosensitizing agents that may be considered include docetaxel and paclitaxel with or without carboplatin.535,537,554,558 Although optimal results have been reported with hyperfractionated EBRT combined with chemotherapy, the NCCN Panel acknowledges that considerable toxicity is associated with such treatment and that prolonged remission is uncommonly reported.559 Multimodality therapy is recommended in patients with locally resectable disease (see Treatment in the NCCN Guidelines for Anaplastic [Thyroid] Carcinoma).510,538,553,560-564 Small retrospective studies have reported that Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
- 107. Version 3.2022 ©2022 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Guidelines Version 3.2022 Thyroid Carcinoma MS-41 patients with ATC who receive trimodal therapy including surgery, radiation, and systemic therapy demonstrate improved survival compared to those who undergo less aggressive treatment approaches.565,566 In a case series, complete surgical resection without tracheostomy or radical re-resection was achieved in six patients with initially unresectable BRAF V600E-mutated anaplastic thyroid carcinoma who received neoadjuvant dabrafenib/trametinib.567 One-year OS was 83%, and the local control rate (LCR) was 100%. Two patients eventually died from distant metastasis, but the treatment response continued to be durable in the remaining four patients. Printed by Cristian Díaz rojas on 12/6/2022 11:33:44 PM. For personal use only. Not approved for distribution. Copyright © 2022 National Comprehensive Cancer Network, Inc., All Rights Reserved.
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